WO2022085791A1 - 老化により機能低下した骨格筋の筋機能改善剤 - Google Patents
老化により機能低下した骨格筋の筋機能改善剤 Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
Definitions
- the present invention relates to a muscle function improving agent for skeletal muscle whose function has deteriorated due to aging.
- the treatment for primary sarcopenia which is mainly caused by aging, is effective because it mainly suppresses muscle weakness by nutrition therapy such as protein and amino acid intake and exercise therapy (rehabilitation).
- nutrition therapy such as protein and amino acid intake and exercise therapy (rehabilitation).
- No remedy has been found.
- Non-Patent Documents 2 to 4 The usefulness of cell therapy, growth factor therapy, and gene therapy using microRNA (miRNA) has been reported as a conventional technique effective for skeletal muscle regeneration.
- problems such as spontaneous malignant transformation of stem cells, limitation of administration method, instability of effective concentration in vivo, immune reaction, off-target effect by therapeutic miRNA, and high cost in manufacturing and quality control. Yes, it has not been clinically applied.
- the present inventors have angiogenic ability and type III for a peptide consisting of 7 amino acids (SVVYGLR: SEQ ID NO: 1) existing in osteopontin (OPN), which is a kind of extracellular matrix (hereinafter referred to as "SV peptide"). It has already been clarified that it has multiple functions such as promotion of collagen secretion and promotion of differentiation from fibroblasts to myofibroblasts (Non-Patent Documents 5 and 6 and Patent Documents 1 to 4).
- the SV peptide has a low molecular weight and low antigenicity, and is highly safe for biological application as compared with the prior art.
- Non-Patent Document 7 and Patent Document 5 disclose SV peptide promotes muscle tissue regeneration by local administration in an injured skeletal muscle animal model, and the regenerated muscle fiber diameter shows a significantly high value in terms of morphology, and it is a promising substance for skeletal muscle function regeneration. Proven (Non-Patent Document 7 and Patent Document 5).
- An object of the present invention is to provide a muscle function improving agent that suppresses or improves muscle function deterioration due to aging.
- Skeletal muscle is originally considered to be a tissue with high regenerative ability, but muscle regenerative ability decreases with aging. It is considered that one of the causes of the onset of sarcopenia is that the decrease in muscle regeneration ability cannot compensate for the regeneration from muscle damage caused by injury or the like.
- muscle hygiene cells are activated due to muscle damage or the like, cell proliferation and differentiation into myoblasts occur.
- myosatellite cells have pluripotency, but their differentiation into myoblasts is determined by activation and expression of the MyoD gene. Myoblasts repeat proliferation to secure the number of cells required for muscle regeneration.
- the expression of the Myogenin gene which is a downstream gene, is induced, and the Myogenin gene is involved in the differentiation and maintenance of myoblasts into myoblasts, and mature muscle cells are formed.
- Muscle cells promote the regeneration of muscle tissue by fusing with muscle fibers.
- some myoblasts enter the quiescent phase of the cell cycle again and return to muscle hygiene cells to control the number of muscle hygiene cells inherent in skeletal muscle.
- muscle hygiene cells have a decrease in the number of cells and a decrease in self-renewal ability due to an endogenous change in the cell itself and an extrinsic change such as a decrease in growth factors with aging.
- the decrease in muscle regeneration ability due to this is considered to be one of the causes of the onset of sarcopenia.
- the present inventors have confirmed that local injection of SV peptide into the muscles of the lower limbs can suppress or ameliorate the decline in muscle function associated with aging in an aging-accelerated model mouse.
- the present invention is an invention completed based on the above findings and includes the following aspects:
- the present invention is in one aspect. [1]
- a muscle function improving agent containing at least one peptide selected from the following (1) to (3) or a salt thereof as an active ingredient: (1) A peptide consisting of the amino acid sequence shown in SEQ ID NO: 1 and (2) A peptide which is a fragment of human osteopontin and whose C-terminal amino acid sequence is the amino acid sequence shown in SEQ ID NO: 1, and (3) Muscle hygiene cells in skeletal muscle associated with aging, consisting of an amino acid sequence in which one to several amino acids are deleted, substituted or added in the amino acid sequence of the peptide in (1) or (2) above. A peptide that has the effect of suppressing or ameliorating the decrease in number. Moreover, in one embodiment, the muscle function improving agent of the present invention is used.
- the muscle function improving agent according to the above [1].
- the following peptides are composed of amino acid sequences in which one to several amino acids are substituted, added or deleted, and have an action of suppressing or ameliorating the functional deterioration of skeletal muscle due to aging.
- X 1 -X 2 -Val- (Tyr / Phe / Trp) -X 5 -X 6 -X 7 (I) (In the formula, X 1 , X 2 , X 5 , X 6 and X 7 represent the same or different amino acid residues.) X 1 -X 2 -Val- (Tyr / Phe / Trp) -X 5 -X 6 (II) (In the formula, X 1 , X 2 , X 5 and X 6 represent the same or different amino acid residues.) X 2 -Val- (Tyr / Phe / Trp) -X 5 -X 6 -X 7 (III) (In the formula, X 2 , X 5 , X 6 and X 7 represent the same or different amino acid residues.) X 1 -X 2 -Val- (Tyr / Phe / Trp) -X 5 -X 6 -X 7 -X 8
- a muscle atrophy inhibitor for suppressing or ameliorating muscle atrophy of fast and / or slow muscle fibers due to aging A muscle atrophy inhibitor containing at least one peptide selected from the following (1) to (3) or a salt thereof as an active ingredient: (1) A peptide consisting of the amino acid sequence shown in SEQ ID NO: 1 and (2) A peptide which is a fragment of human osteopontin and whose C-terminal amino acid sequence is the amino acid sequence shown in SEQ ID NO: 1, and (3) In the amino acid sequence of the peptide in (1) or (2) above, one to several amino acids are deleted, substituted or added to the amino acid sequence, and fast muscle fibers and / or slow muscles due to aging are formed.
- the muscular atrophy inhibitor of the present invention is, in one embodiment, [4] The muscular atrophy inhibitor according to the above [3].
- the peptide having such an action is a peptide having any of the following amino acid sequences (I) to (IV).
- a muscle atrophy inhibitor wherein the peptide having such an action is a fragment of human osteopontin, and the amino acid sequence at the C-terminal of the fragment is a peptide having any of the following amino acid sequences (I) to (IV).
- X 1 -X 2 -Val- (Tyr / Phe / Trp) -X 5 -X 6 -X 7 (I) (In the formula, X 1 , X 2 , X 5 , X 6 and X 7 represent the same or different amino acid residues.) X 1 -X 2 -Val- (Tyr / Phe / Trp) -X 5 -X 6 (II) (In the formula, X 1 , X 2 , X 5 and X 6 represent the same or different amino acid residues.) X 2 -Val- (Tyr / Phe / Trp) -X 5 -X 6 -X 7 (III) (In the formula, X 2 , X 5 , X 6 and X 7 represent the same or different amino acid residues.) X 1 -X 2 -Val- (Tyr / Phe / Trp) -X 5 -X 6 -X 7 -X 8
- the muscle function improving agent of the present invention is used.
- a muscle function improving agent for suppressing or improving the functional deterioration of skeletal muscle is used in combination with a stimulus load, and A muscle function improving agent containing at least one peptide selected from the following (1) to (3) or a salt thereof as an active ingredient: (1) A peptide consisting of the amino acid sequence shown in SEQ ID NO: 1 and (2) A peptide which is a fragment of human osteopontin and whose C-terminal amino acid sequence is the amino acid sequence shown in SEQ ID NO: 1, and (3) In the amino acid sequence of the peptide in the above (1) or (2), one to several amino acids are deleted, substituted or added to the amino acid sequence, and the deterioration of skeletal muscle function is suppressed or improved. A peptide with action.
- the function of skeletal muscle deteriorated due to aging can be improved.
- FIG. 1 shows the number of collisions during treadmill running after local injection of SV peptide into bilateral lower limb muscles after treadmill administration from 22 weeks to 35 weeks of age in the Society for Senescence Acceleration. It is a graph which shows.
- the control group shows the group in which PBS was locally injected instead of the SV peptide.
- FIG. 2 shows a 36-week-old age-accelerated model mouse in which the SV peptide was locally injected into the muscles of both lower limbs after the treadmill was performed, and the treadmill was run 12 hours, 24 hours, or 72 hours after the local injection. It is a graph which shows the number of collisions of.
- the control group shows the group in which PBS was locally injected instead of the SV peptide.
- FIG. 1 shows the number of collisions during treadmill running after local injection of SV peptide into bilateral lower limb muscles after treadmill administration from 22 weeks to 35 weeks of age in the Society for Senescence Acceleration. It is a graph which shows.
- the control group shows the group in which PBS
- FIG. 3A shows the results of HE staining of the gastrocnemius muscle (fast muscle) of the Society for Senescence Acceleration model mice in which SV peptide was locally injected into the bilateral lower limb muscles after treadmilling from 22 weeks to 40 weeks.
- FIG. 3B shows the average muscle fibers of the gastrocnemius muscle (fast muscle) and soleus muscle (slow muscle) of the Society for Senescence Acceleration model mice in which SV peptide was locally injected into the bilateral lower limb muscles after tread milling from 22 weeks to 40 weeks.
- the graph of the cross-sectional area is shown.
- the control group shows the group in which PBS was locally injected instead of the SV peptide.
- FIG. 4 shows a graph showing the relationship between the elapsed time adopted in the endurance evaluation test conducted in Example 4 below and the increase in belt speed, and the relationship between the elapsed time adopted in the slope-up evaluation test and the increase in belt inclination. The graph shown is shown.
- FIG. 5 shows the SV group (training and SV peptide administration group), the SVN group (SV peptide administration group), and the PBS group (training and PBS administration group) in the endurance evaluation test conducted in Example 4 below. It is a graph which shows the rate of change of the average mileage.
- FIG. 5 shows the SV group (training and SV peptide administration group), the SVN group (SV peptide administration group), and the PBS group (training and PBS administration group) in the endurance evaluation test conducted in Example 4 below. It is a graph which shows the rate of change of the average mileage.
- FIG. 5 shows the SV group (training and SV peptide administration group), the SVN group (SV peptide administration group), and the PBS
- FIG. 6 shows the SV group (training and SV peptide administration group), the SVN group (SV peptide administration group), and the PBS group (training and PBS administration group) in the endurance evaluation test conducted in Example 4 below. It is a graph which shows the time-dependent change of the average work load.
- FIG. 7 shows the change over time in the average mileage of the SV group (training performed and SV peptide administration group) and the PBS group (training performed and PBS administration group) with respect to the reference date in the endurance evaluation test conducted in Example 5 below. It is a graph which shows.
- the arrows in FIG. 7 indicate the difference in the amount of change in the average mileage between the SV group and the PBS group (indicating the effect of SV administration).
- FIG. 7 shows the change over time in the average mileage of the SV group (training performed and SV peptide administration group) and the PBS group (training performed and PBS administration group) with respect to the reference date in the endurance evaluation test conducted in Example 5 below. It is a graph which shows
- FIG. 8 shows the change over time of the fastest average of the SV group (training and SV peptide administration group) and the PBS group (training and PBS administration group) in the endurance evaluation test conducted in Example 5 below with respect to the reference date. It is a graph which shows.
- FIG. 9 shows the average muscle fibers of the gastrocnemius muscle, extensor digitorum longus muscle, and tibialis anterior muscle of the Society for Senescence Acceleration model mice in which SV peptide was locally injected into the bilateral lower limb muscles from 28 weeks to 51 weeks of age. The graph of the cross-sectional area is shown.
- the control group shows the group in which PBS was locally injected instead of the SV peptide.
- FIG. 9 shows the average muscle fibers of the gastrocnemius muscle, extensor digitorum longus muscle, and tibialis anterior muscle of the Society for Senescence Acceleration model mice in which SV peptide was locally injected into the bilateral lower limb muscles from 28 weeks to
- FIG. 10 shows the average muscle fibers of type I, type IIa, and type IIb in the gastrocnemius muscle of an aging-accelerated model mouse in which SV peptide was locally injected into the muscles of both lower limbs after treadmilling from 28 weeks to 51 weeks.
- the graph of the cross-sectional area is shown.
- the control group shows the group in which PBS was locally injected instead of the SV peptide.
- FIG. 11 shows the results of HE staining of the gastrocnemius muscle (fast muscle) of the Society for Senescence Acceleration Model Mouse in which SV peptide was locally injected into the bilateral lower limb muscles after treadmilling from 28 weeks to 51 weeks.
- FIG. 12 is a graph showing changes over time in the average mileage of the SV group (training performed and SV peptide administration group) and the PBS group (training performed and PBS administration group) in the endurance evaluation test conducted in Example 6 below. be.
- FIG. 13 shows the amount of change in the average mileage of the SV group (training performed and SV peptide administration group) and the PBS group (training performed and PBS administration group) with respect to the reference date in the endurance evaluation test conducted in Example 6 below over time. It is a graph showing a target.
- FIG. 14 is a graph showing changes over time in the average mileage of the SV group (training performed and SV peptide administration group) and the PBS group (training performed and PBS administration group) in the endurance evaluation test conducted in Example 7 below. be.
- FIG. 15 shows the amount of change in the average mileage of the SV group (training performed and SV peptide administration group) and the PBS group (training performed and PBS administration group) with respect to the reference date in the endurance evaluation test conducted in Example 7 below over time. It is a graph showing a target.
- FIG. 16 shows the amount of change in the average mileage of the SV group (training performed and SV peptide administration group) and the PBS group (training performed and PBS administration group) with respect to the reference date in the endurance evaluation test conducted in Example 7 below. It is a graph showing a target.
- FIG. 17 is a graph showing changes over time in the average maximum speed of the SV group (training and SV peptide administration group) and the PBS group (training and PBS administration group) in the endurance evaluation test conducted in Example 7 below.
- FIG. 19 shows the change in the maximum speed average of the SV group (training and SV peptide administration group) and the PBS group (training and PBS administration group) with respect to the reference date in the endurance evaluation test conducted in Example 7 below over time. It is a graph showing a target.
- FIG. 19 shows the change in the maximum speed average of the SV group (training and SV peptide administration group) and the PBS group (training and PBS administration group) with respect to the reference date in the endurance evaluation test conducted in Example 7 below over time. It is a graph showing a target.
- the present invention is, in one embodiment, a muscle function improving agent for suppressing or ameliorating the functional deterioration of skeletal muscle due to aging.
- a muscle function improving agent containing at least one peptide selected from the following (1) to (3) or a salt thereof as an active ingredient: (1) A peptide consisting of the amino acid sequence shown in SEQ ID NO: 1 and (2) A peptide which is a fragment of human osteopontin and whose C-terminal amino acid sequence is the amino acid sequence shown in SEQ ID NO: 1, and (3)
- a peptide that has an inhibitory or ameliorating effect are substituted, added, or deleted amino acid sequences, and skeletal muscle function declines due to aging due to aging.
- “Deterioration of skeletal muscle function due to aging” means that the function of skeletal muscle is reduced due to the deterioration of physiological function. For example, skeletal muscle mass is reduced due to a decrease in muscle regeneration ability of cells (muscle hygiene cells, myoblasts, or muscle cells) that compose skeletal muscle due to aging, and the function of contracting or relaxing muscle fibers is reduced. Means the state.
- “Skeletal muscle dysfunction due to aging” refers to diseases other than aging such as genetic factors, inactivity, organ failure, and nutritional status, as long as skeletal muscle function declines due to physiologic function decline. It also includes a state in which the function of skeletal muscle is reduced due to the cause.
- the amino acid sequence of human osteopontin includes, for example, the amino acid sequence shown in SEQ ID NO: 11, but is not limited thereto.
- Human osteopontin contains the amino acid sequence set forth in SEQ ID NO: 1 (SVVYGLR), and thrombin cleaves human osteopontin immediately after SVVYGLR in the amino acid sequence set forth in SEQ ID NO: 11 and has a sequence of SVVYGLR at the C-terminus. Occurs.
- the "fragment of human osteopontin” is such a fragment (SEQ ID NO: 12) or a part thereof, and has a sequence of SVVYGLR at the C-terminal.
- a protein having the same structure and function as human osteopontin can be referred to as human osteopontin, and its amino acid sequence is the amino acid sequence of human osteopontin.
- the length of the fragment of human osteopontin is not particularly limited, but the total number of amino acid residues is preferably about 170 or less, more preferably about 150 or less, and further preferably about 100 or less. Further, from the viewpoint of side effects such as ease of handling, production efficiency, and antigenicity, the total number of amino acid residues is preferably about 50 or less, more preferably about 30 residues or less, and about 20 residues. The following is more preferable, and it is particularly preferable that the number of residues is about 10 or less.
- amino acid sequence in which one to several amino acids are deleted, substituted or added is deleted or substituted (preferably) by a known mutant peptide preparation method such as a site-specific mutagenesis method.
- Conservative substitution or a number of amino acids that can be added (preferably 10 or less, more preferably 7 or less, still more preferably 5, 4, 3, 2, 1, 1) are deleted, substituted or deleted. Means to be added.
- amino acid sequences that are at least 80% identical include amino acid sequences that are at least 85%, 90%, 92%, 95%, 96%, 97%, 98% or 99% identical. Amino acids functionally similar to specific amino acids as conservative substitutions are well known in the art.
- amino acid side chain properties are hydrophobic amino acids (A, I, L, M, F, P, W, Y, V), hydrophilic amino acids (R, D, N, C, E, Q, G, H, K, S, T), and side chains with the following common functional groups or characteristics: aliphatic side chains (G, A, V, L, I, P); hydroxyl group-containing side chains (S, T). , Y); sulfur atom-containing side chains (C, M); carboxylic acid and amide-containing side chains (D, N, E, Q); base-containing side chains (R, K, H); and aromatic-containing side chains. (H, F, Y, W).
- the following eight groups each contain amino acids that are conservative substitutions with each other: 1) alanine (A), glycine (G); 2) aspartic acid (D), glutamic acid (E); 3) aspartin (N), Glutamine (Q); 4) arginine (R), lysine (K); 5) isoleucine (I), leucine (L), methionine (M), valine (V); 6) phenylalanine (F), tyrosine (Y) , Tryptophan (W); 7) Serine (S), Threonine (T); and 8) Cysteine (C), Methionine (M) (see, eg, Crewton, Proteins 1984).
- the amino acid sequence of the peptide consisting of the amino acid sequence shown in SEQ ID NO: 1 one to several amino acids are substituted, added, or deleted amino acid sequences, and the skeletal muscle function is deteriorated due to aging.
- the peptide having an action of suppressing or ameliorating the above include a peptide having the amino acid sequence of any of the following (I) to (IV): X 1 -X 2 -Val- (Tyr / Phe / Trp) -X 5 -X 6 -X 7 (I) (In the formula, X 1 , X 2 , X 5 , X 6 and X 7 represent the same or different amino acid residues.) X 1 -X 2 -Val- (Tyr / Phe / Trp) -X 5 -X 6 (II) (In the formula, X 1 , X 2 , X 5 and X 6 represent the same or different amino acid residues.) X 2 -
- X 5 is glycine or its conservative substitution amino acid
- X 6 is leucine or its conservative substitution amino acid
- X 7 is arginine or its conservative substitution amino acid.
- the peptide consisting of the amino acid sequence of any of the above (I) to (IV) has several more amino acids at its N-terminal or C-terminal as long as it has an action of suppressing or ameliorating the functional deterioration of skeletal muscle due to aging. May have.
- amino acid sequence of the peptide consisting of the amino acid sequence shown in SEQ ID NO: 1 one to several amino acids are substituted, added or deleted amino acid sequences, and the function of skeletal muscle due to aging
- amino acids having an action of suppressing or ameliorating the decrease include peptides consisting of the amino acids shown in (V) below: X 1 -Val-Val- (Tyr / Phe / Trp) -X 5 -X 6 -X 7 (V)
- amino acid sequence of the peptide consisting of the amino acid sequence shown in SEQ ID NO: 1 one to several amino acids are substituted, added, or deleted amino acid sequences, and the skeletal muscle due to aging
- amino acids having an action of suppressing or ameliorating the functional deterioration include peptides consisting of the amino acids shown in SEQ ID NOs: 2 to 10 below:
- the present inventors have a peptide in which the C-terminal R of SVVYGLR (SEQ ID NO: 1) is deleted (SEQ ID NO: 4) and a peptide in which the N-terminal S is deleted (SEQ ID NO: 1). It has been confirmed that the peptide (SEQ ID NO: 10) in which an amino acid is added to the C-terminal of SEQ ID NO: 5) and SVVYGLR (SEQ ID NO: 1) is also maintained.
- the present inventors have a peptide in which the angiogenic action of SVVYGLR (SEQ ID NO: 1) replaces amino acids other than the fourth tyrosine (Y) in SEQ ID NO: 1 with alanine one by one (for example, SEQ ID NO: 2, It has been confirmed that it will be maintained even in 3 and 4).
- the present inventors confirmed that the osteopontin fragment having SVVYGLR (SEQ ID NO: 1) at the C-terminal has an action equivalent to that of SVVYGLR (SEQ ID NO: 1) on fibroblasts to promote type III collagen production. (See Patent Document 1). It can be reasonably inferred that all of the peptides (1) to (3) have an action as a muscle function improving agent.
- one to several amino acids have been substituted, added or deleted in the amino acid sequence of a peptide which is a fragment of human osteopontin and whose C-terminal amino acid sequence is the amino acid sequence shown in SEQ ID NO: 1.
- a peptide consisting of an amino acid sequence and having an action of suppressing or ameliorating the functional deterioration of skeletal muscle due to aging an amino acid sequence portion at the C-terminal, an amino acid sequence portion other than the C-terminal, or both amino acids
- one to several amino acids contain a fragment of human osteopontin substituted, added or deleted.
- the amino acid constituting the peptide which is the active ingredient of the muscle function improving agent of the present invention may have a side chain modified with an arbitrary substituent.
- the substituent is not particularly limited, and examples thereof include a fluorine atom, a chlorine atom, a cyano group, a hydroxyl group, a nitro group, an alkyl group, a cycloalkyl group, an alkoxy group, and an amino group.
- the benzene ring of tryptophan or phenylalanine is modified with a substituent.
- the peptide which is the active ingredient of the muscle function improving agent of the present invention may have a C-terminal of any of a carboxyl group (-COOH), a carboxylate (-COO-), an amide (-CONH2) or an ester (-COOR). good.
- R in the ester for example, a C1-6 alkyl group such as methyl, ethyl, n-propyl, isopropyl or n-butyl, for example, a C3-8 cycloalkyl group such as cyclopentyl, cyclohexyl, for example, phenyl, ⁇ -naphthyl.
- C6-12 aryl groups such as C6-12 aryl groups such as phenyl-C1-2 alkyl groups such as benzyl and phenethyl or ⁇ -naphthyl-C1-2 alkyl groups such as ⁇ -naphthylmethyl, as well as C7-14 aralkyl groups for oral use.
- Examples thereof include a pivaloyloxymethyl group commonly used as an ester.
- the amide compound include amides, amides substituted with one or two of C1-6 alkyl groups, amides substituted with one or two of C1-6 alkyl groups substituted with phenyl groups, and amide groups.
- Examples thereof include amides containing the nitrogen atom of the above to form a 5- to 7-membered ring of azacycloalkanes.
- the peptide of the present invention has a carboxyl group or a carboxylate other than the C-terminal, those in which those groups are amidated or esterified are also included in the peptide of the present invention.
- the N-terminal amino group is a protective group (for example, a formyl group, a C1-6 acyl group such as a C2-6 alkanoyl group such as acetyl).
- a protective group for example, a formyl group, a C1-6 acyl group such as a C2-6 alkanoyl group such as acetyl.
- suitable protective groups eg, formyl groups, C1-6 acyl groups such as C2-6 alkanoyl groups such as acetyl. Things are also included.
- the peptide which is the active ingredient of the muscle function improving agent of the present invention may form a salt, and the salt thereof is preferably a pharmaceutically acceptable salt.
- Pharmaceutically acceptable salts include, for example, salts with acids such as hydrochloric acid, sulfuric acid, phosphoric acid, lactic acid, tartaric acid, maleic acid, fumaric acid, oxalic acid, malic acid, citric acid, oleic acid, palmitic acid; sodium.
- Salts with alkali metals such as potassium, calcium or alkaline earth metals, or salts with hydroxides or carbonates of aluminum; salts with triethylamine, benzylamine, diethanolamine, t-butylamine, dicyclohexylamine, arginine, etc. Can be mentioned.
- the peptide or salt thereof which is the active ingredient of the muscle function improving agent of the present invention, can be produced by a solid phase synthesis method (Fmoc method, Boc method) or a liquid phase synthesis method according to a known general peptide synthesis protocol. can. Further, it can be produced by using a transformant into which an expression vector containing a DNA encoding a target peptide has been introduced. It can also be manufactured by a method using an in vitro transcription / translation system.
- Targets of aged skeletal muscle whose function can be improved by the muscle function improving agent of the present invention include, for example, sarcopenia and / or skeletal muscle having muscular atrophy or muscle degeneration with aging, skeletal muscle having inclusion body myositis, and the like. Examples include muscular atrophy promoted by skeletal swelling after surgery such as femoral neck fracture surgery.
- Sarcopenia is defined by a decrease in skeletal muscle mass and a decrease in muscle strength or physical function due to aging or the like. There are multiple reports on the criteria for sarcopenia, for example, the 2017 edition of the Sarcopenia Practice Guidelines (publisher: National Center for Geriatrics and Gerontology, Japan Sarcopenia-Frail Society).
- sarcopenia includes primary sarcopenia associated with aging and secondary sarcopenia associated with causes other than aging (sarcopenia associated with activities such as lack of activity, organ failure, inflammatory diseases, malignant tumors, endocrine diseases, etc.) It is classified as disease-related sarcopenia, including nutrition-related sarcopenia such as undernourishment).
- the muscle function improving agent of the present invention can be treated for both primary sarcopenia and secondary sarcopenia.
- skeletal muscle atrophy examples include, but are not limited to, lower limb muscle atrophy, lower limb muscle atrophy, muscular atrophy, scapulohumeral atrophy, limb muscle atrophy, upper limb muscle atrophy, systemic muscle atrophy, Examples include mitral muscle atrophy, degenerative muscle atrophy, disuse syndrome, disuse muscle atrophy, and finger ball muscle atrophy.
- the muscle function improving agent of the present invention can be implemented as a medicine, cosmetics, or food for improving the function of skeletal muscle whose function has deteriorated due to aging. That is, as another aspect of the present invention, it is possible to provide a pharmaceutical composition, cosmetics, food and drink composition containing the muscle function improving agent of the present invention.
- the muscular function improving agent of the present invention can be appropriately blended with a pharmaceutically acceptable carrier or additive to form a formulation.
- oral preparations such as tablets, coated tablets, pills, powders, granules, capsules, liquids, suspensions, emulsions; non-injections, microneedles, infusions, suppositories, ointments, patches, etc.
- the blending ratio of the carrier or the additive may be appropriately set based on the range usually adopted in the pharmaceutical field or the cosmetic field.
- the carriers or additives that can be blended are not particularly limited, but are various carriers such as water, physiological saline, other aqueous solvents, aqueous or oily bases; excipients, binders, pH adjusters, disintegrants, absorption. Examples thereof include various additives such as accelerators, lubricants, colorants, flavoring agents and fragrances. When implemented as a food and drink composition, it can be prepared by appropriately blending carriers and additives usually used in the food and drink field.
- Additives that can be mixed with tablets, capsules, etc. include, for example, gelatin, cornstarch, tragant, binders such as gum arabic, excipients such as crystalline cellulose, cornstarch, gelatin, arginic acid and the like. Binders, lubricants such as magnesium stearate, sweeteners such as sucrose, lactose or saccharin, flavors such as peppermint, reddish oil or cherry are used.
- the dispensing unit form is a capsule, the above-mentioned type of material can further contain a liquid carrier such as oil and fat.
- Sterile compositions for injection can be formulated according to routine formulation practices such as dissolving or suspending active substances in vehicles such as water for injection, naturally occurring vegetable oils such as coconut oil, coconut oil and the like.
- aqueous solution for injection for example, a physiological saline solution, an isotonic solution containing glucose and other auxiliary agents (for example, D-sorbitol, D-mannitol, sodium chloride, etc.) and the like are used, and appropriate solubilizing agents are used.
- it may be used in combination with alcohol (eg, ethanol), polyalcohol (eg, propylene glycol, polyethylene glycol), nonionic surfactant (eg, polysorbate 80TM, HCO-50) and the like.
- oily liquid for example, sesame oil, soybean oil and the like are used, and may be used in combination with benzyl benzoate, benzyl alcohol and the like as solubilizing agents.
- buffers eg, phosphate buffer, sodium acetate buffer
- soothing agents eg, benzalconium chloride, procaine hydrochloride, etc.
- stabilizers eg, human serum albumin, polyethylene glycol, etc.
- an agent for example, benzyl alcohol, phenol, etc.
- an antioxidant or the like.
- the muscle function improving agent of the present invention may be implemented as an injection or a microneedle for direct administration to the target skeletal muscle or the muscle around it (skeletal muscle), and may be applied to the skeletal muscle or the muscle around it. It may be carried out as an ointment or patch for application or application.
- the microneedle technique is a patch-type transdermal preparation that administers a drug into the body by containing the drug in the tip of the fine needle and attaching it to the skin.
- the muscle function improving agent of the present invention can be used in combination with a known microneedle technique.
- the muscle function improving agent of the present invention may be in the form of a peptide as an active ingredient bound to a carrier.
- the carrier is not particularly limited, and examples thereof include resins used for artificial organs and biopolymers such as proteins. Above all, it is preferable to carry out in the form of a bioabsorbable gel containing a peptide as an active ingredient.
- bioabsorbable gel for example, a known bioabsorbable hydrogel can be preferably used.
- a known bioabsorbable hydrogel can be preferably used.
- Specific examples thereof include, but are not limited to, the hydrogel for sustained release "Medgel (trade name)" manufactured by Medgel Co., Ltd.
- This product is made by cross-linking gelatin and insolubilizing it in water, and can retain peptides by intramolecular interaction centered on electrostatic interaction force with gelatin.
- the gelatin hydrogel retains a peptide as an active ingredient and is applied to a living body, the gelatin hydrogel is decomposed by a degrading enzyme such as collagenase secreted from cells. The peptide is slowly released with decomposition, and the decomposition product is absorbed by the living body.
- the shape of the bioabsorbable gel is not particularly limited, and can be implemented in various shapes such as a sheet shape, a disc shape, a tube shape, and a particle shape.
- the bioabsorbable gel can be applied or affixed to the damaged site of skeletal muscle and used.
- the peptide or salt thereof which is the active ingredient of the muscle function improving agent of the present invention, is safe and has low toxicity, for example, humans and other mammals (eg, rats, mice, rabbits, sheep, pigs, cows, cats). , Dogs, monkeys, etc.).
- the dose varies depending on the site of functional deterioration, administration route, etc., but for example, when injected intramuscularly around the skeletal muscle with reduced function in adults, the daily dose of the active ingredient is about 0.00001. It may be up to 100 mg, about 0.00002 to 90 mg, about 0.00005 to 80 mg, about 0.0001 to 50 mg, about 0.01 to 30 mg. It may be about 0.1 to 20 mg, or it may be about 0.1 to 10 mg.
- the muscle function improving agent of the present invention is, for example, daily (once a day, twice a day, three times a day, four times a day, five times a day, six times a day), 2 Once daily, once every three days, once every four days, once every five days, once every six days, every week, twice a week, every other week, once every three weeks, once every four weeks It can be administered once a month, once every two months, once every three months, once every four months, once every five months or once every six months.
- the muscle function improving agent of the present invention can be provided as a muscle function improving agent to be used in combination with a load of stimulation to a functionally deteriorated skeletal muscle.
- the muscle function improving agent according to the present invention is used in combination with the load of stimulation to the skeletal muscle, the function of the skeletal muscle is further reduced when the muscle function improving agent is used alone or as compared with the stimulation load on the skeletal muscle alone. It can be suppressed.
- the muscle function improving agent according to the present invention can exhibit an excellent muscle function improving effect that cannot be obtained when the muscle function improving agent is used alone or when the stimulating load on the skeletal muscle is used alone. ..
- the "load of stimulus on skeletal muscle” is not limited as long as it is a load of stimulus that induces muscle contraction and / or muscle relaxation of skeletal muscle.
- a known stimulation loading method can be adopted.
- Stimulation load by exercise therapy, etc. load by physiological muscle stimulation method (for example, electrical stimulation method (neuromuscular electrical stimulation method: NMES) (Jpn J Rehabil Med 2017; 54: 764-767)), vibration, but not limited to the following. (For example, see Patent No. 6886559) and the like.
- “Exercise load on skeletal muscle with reduced function” is not limited as long as it can suppress or improve the functional deterioration of skeletal muscle when used in combination with the muscle function improving agent of the present invention, and is not limited to the following, but for example, sarcopenia.
- known exercise therapies used to treat sarcopenia can be employed.
- a preferable exercise load method can be appropriately set according to the target age and health condition, and the target skeletal muscle and skeletal muscle mass. Specific examples of the exercise load method include squats, knee extension, and knee raising when the quadriceps muscle is the target, and one-leg standing exercise when the gluteus maxims muscle is the target, and the gastrocnemius muscle.
- the "load of stimulation on the skeletal muscle with reduced function" is defined as before the administration of the muscle function improving agent of the present invention (for example, 30 minutes before, 1 hour before, 2) as long as the functional deterioration of the skeletal muscle due to aging can be suppressed or ameliorated.
- Hours before, 6 hours before, 12 hours before, 1 day before, etc. at the time of administration, after administration (for example, 30 minutes after, 1 hour, 2 hours, 6 hours, 12 hours, 1 day, etc.) It may be done at the time of.
- the muscle function improving agent of the present invention is administered after or at the same time as the stimulation load on the skeletal muscle.
- the present invention can be provided as a muscle function improving agent for suppressing or ameliorating the functional deterioration of skeletal muscle or for repairing muscle damage of skeletal muscle.
- the muscle function improving agent is used in combination with the load of stimulation to the skeletal muscle, and contains at least one peptide selected from the following (1) to (3) or a salt thereof as an active ingredient.
- Is (1) A peptide consisting of the amino acid sequence shown in SEQ ID NO: 1 and (2) A peptide which is a fragment of human osteopontin and whose C-terminal amino acid sequence is the amino acid sequence shown in SEQ ID NO: 1, and (3) In the amino acid sequence of the peptide in the above (1) or (2), one to several amino acids are deleted, substituted or added to the amino acid sequence, and the deterioration of skeletal muscle function is suppressed or improved. A peptide with action.
- the muscle function improving agent of the present invention is used in combination with a stimulating load on the skeletal muscle, and in addition to the skeletal muscle whose function has deteriorated due to aging, for example, skeletal muscle such as muscle rupture, muscle atrophy, and muscle degeneration. Repair the damage or improve the function of the skeletal muscle that was impaired by the damage.
- skeletal muscle damage include muscle rupture, muscle atrophy, and muscle degeneration.
- muscle rupture associated with major trauma muscle rupture associated with surgery, muscle rupture associated with trauma such as fracture / bruise / meat separation, muscle damage of athletes, postoperative muscle rupture or atrophy of ligaments, artificial hip joint Progression in hereditary neuromuscular diseases such as muscular rupture or atrophy after surgery, disused muscular atrophy due to decreased motor units after head and neck surgery requiring long-term closure, muscular atrophy associated with cancerous fluid quality, and muscular dystrophy
- hereditary neuromuscular diseases such as muscular rupture or atrophy after surgery, disused muscular atrophy due to decreased motor units after head and neck surgery requiring long-term closure, muscular atrophy associated with cancerous fluid quality, and muscular dystrophy
- sexual muscle atrophy muscle atrophy associated with spinal orthostatic muscle disorder, muscle atrophy associated with lumbar disc hernia, muscle atrophy associated with neck descent syndrome, encapsulation myitis, fibrosis / scar contraction after surgery with extensive muscle resection, palatal Examples include scar atrophy accompanied by motor dysfunction after plastic surgery for congenital muscular abnormalities such as fissures
- the present invention is a muscle fiber hypertrophy promoter for enlarging fast muscle fibers and / or slow muscle fibers that have been atrophied due to aging.
- a muscle fiber hypertrophy promoter containing at least one peptide selected from the following (1) to (3) or a salt thereof as an active ingredient: (1) A peptide consisting of the amino acid sequence shown in SEQ ID NO: 1 and (2) A peptide which is a fragment of human osteopontin and whose C-terminal amino acid sequence is the amino acid sequence shown in SEQ ID NO: 1, and (3) Muscle hygiene cells in skeletal muscle associated with aging, consisting of an amino acid sequence in which one to several amino acids are deleted, substituted or added in the amino acid sequence of the peptide in (1) or (2) above.
- the present invention is a muscle regeneration ability improving agent for improving the decrease in muscle regeneration ability of skeletal muscle due to aging, and is at least one peptide selected from the above (1) to (3) or A muscle regeneration ability improving agent containing the salt is provided.
- the muscle fiber hypertrophy promoting agent and the muscle regenerating ability improving agent of the present invention can be carried out in the same manner as in the above-described embodiment of the muscle function improving agent of the present invention.
- the present invention further includes the following inventions.
- (A1) Skeletal muscle due to aging which comprises administering a therapeutically effective amount of at least one peptide selected from the above (1) to (3) or a salt thereof to a subject having skeletal muscle whose function has deteriorated due to aging. How to improve the functional deterioration of.
- (A1'') The method for improving skeletal muscle function deterioration due to aging according to (a1) above, wherein the peptide or a salt thereof is administered to the skeletal muscle whose function has deteriorated due to aging or the surrounding skeletal muscle.
- a method for improving skeletal muscle function deterioration due to aging which is characterized by the fact that (A2) A therapeutically effective amount of at least one peptide selected from the above (1) to (3) or a salt thereof is administered to a subject having fast muscle fiber and / or slow muscle fiber atrophied by aging.
- (A2') The method for enlarging fast muscle fibers and / or slow muscle fibers atrophied by aging according to the above (a2), wherein the administration is used in combination with a load of stimulation to skeletal muscle. How to improve skeletal muscle function deterioration due to aging.
- (B1) At least one peptide or a salt thereof selected from the above (1) to (3) for use in improving the functional deterioration of skeletal muscle due to aging.
- (B2) At least one peptide selected from the above (1) to (3) or a salt thereof for use in hypertrophy of fast muscle fibers and / or slow muscle fibers that have been atrophied due to aging.
- (C1) Use of at least one peptide selected from the above (1) to (3) or a salt thereof for producing a muscle function improving agent that suppresses or improves the functional deterioration of skeletal muscle due to aging.
- (C2) Of at least one peptide selected from the above (1) to (3) or a salt thereof for producing a muscle fiber hypertrophy promoter that enlarges fast muscle fibers and / or slow muscle fibers that have been atrophied due to aging. use.
- (C1') The peptide or salt thereof according to (b1) above, wherein the peptide or salt thereof is used in combination with a load of stimulation to skeletal muscle.
- Example 1 a peptide (SV peptide) consisting of the amino acid sequence of SVVYGLR (SEQ ID NO: 1) was administered to an aging-accelerated model mouse, and the muscle function recovery effect was confirmed.
- the SV peptide used as the test peptide was synthesized by the Fmoc method using a multi-item solid-phase automatic peptide synthesizer (PSSM-8; Shimadzu Corporation).
- PSSM-8 multi-item solid-phase automatic peptide synthesizer
- the SV peptide was added to PBS and adjusted to 20 ng / ml to prepare an injection. Training was performed using a treadmill (MK-680; manufactured by Muromachi Kikai Co., Ltd.) using an aging-accelerated model mouse (SAMP10 21 weeks old), and subsequent SV peptide administration was performed according to the schedule in the table below.
- mice were subjected to a collision count measurement test using a treadmill. After the SV peptide station injection, the treadmill (18 m / min ⁇ 90 min) was performed again, and when the treadmill was performed, the aging-accelerated model mouse could not run at a speed equal to or higher than the speed of the belt, and it was on the wall of the treadmill. The number of collisions was measured.
- Example 2 In this example, the SV peptide was administered to the aging-accelerated model mice, and the muscle function recovery effect after a certain period of time from the administration was confirmed. Training with a treadmill using an aging-accelerated model mouse (SAMP10 36 weeks old) was performed under the same conditions as the main training of the 35-week-old mice of Example 1, and SV peptide (total 40 ng) was immediately applied after the treadmill. Local injection was performed on both lower limb muscles (experimental group). SV peptide administration was also performed at the same administration site and dose as in the 35-week-old mice of Example 1. Treadmill training (18 m / min x 90 min) was retried 12 hours, 24 hours, or 72 hours after local injection to assess the number of collisions.
- Example 3 muscle fibers were evaluated when SV peptide was continuously administered to the aging-accelerated model mice.
- FIG. 3A shows an HE-stained image of the gastrocnemius muscle in the cross section of the muscle fiber.
- FIG. 3B also shows the average cross-sectional area of the muscle fibers identified as slow muscles in the soleus muscle and the average cross-sectional area of the muscle fibers identified as fast muscles in the gastrocnemius muscle.
- the average muscle fiber cross-sectional area of both fast and slow muscles was significantly higher than that of the control group (Fig. 3B).
- Example 4 exercise was evaluated when SV peptide was continuously administered to the aging-accelerated model mice. Training was performed using a treadmill (MK-680; manufactured by Muromachi Kikai Co., Ltd.) using an aging-accelerated model mouse (SAMP10 28 weeks old), and subsequent SV peptide administration was performed according to the schedule in the table below. After 30 weeks of age, training was continued from Monday to Friday of each week. The SV peptide was added to PBS to a concentration of 1 ⁇ g / ml or 20 ng / ml to adjust the injection and was localized to the bilateral lower limb muscles of each mouse inhaled and anesthetized with sevoflurane immediately after training on Tuesday and Friday. Noted (SV group).
- FIG. 4 shows the relationship between the elapsed time used in the exercise evaluation test and the increase in belt speed or belt inclination.
- the PBS group as in the SV group, after training with a treadmill, PBS was locally injected into the bilateral lower limb muscles instead of the SV peptide.
- the results of the endurance evaluation test are shown in FIG. 5 as a graph of the rate of change in the average mileage.
- the rate of change in the average mileage indicates a relative value when the average mileage in each group at 30 weeks (base date) is 100%.
- the average mileage of each group was calculated as the average value of the mileage calculated from the running time and the running speed of each mouse belonging to each group (hereinafter, the average mileage was calculated in the same manner).
- the rate of change in the average mileage increased to about 130%, and the average mileage increased from the reference date during the measurement period.
- the average mileage decreased over time without exceeding the average mileage on the reference date.
- the rate of change in average mileage was also measured for the group (SVN group) in which the SV peptide was administered at the same administration site and dose at the same timing as the SV group without training using a treadmill.
- the rate of change in the average mileage did not exceed 100% after the reference date, and the average mileage decreased over time (not shown).
- the improvement effect of motor function which cannot be obtained in the PBS group to which only the exercise stimulus was given and the SVN group to which the SV peptide was administered without the exercise stimulus, was confirmed.
- the results of the slope-up evaluation test are shown in FIG. 6 as a graph of the rate of change in the average work load.
- the average work amount is calculated by multiplying the work amount of each mouse belonging to each group by the weight, running time, inclination (grade), running speed, and gravitational acceleration g (9.8 m / s 2 ), and calculating as the average value. bottom.
- the SV-administered group showed a higher workload than the PBS group.
- Example 5 In this example, the training content and the SV peptide administration concentration were changed with respect to Example 4, and exercise evaluation (endurance evaluation) was performed when SV peptide was continuously administered to the aging-accelerated model mice. In addition, the cross-sectional area of muscle fibers (gastrocnemius (type I, type IIa, type IIb), extensor digitorum longus muscle, and tibialis anterior muscle) of mice that continued training and SV peptide administration until 51 weeks of age was evaluated.
- muscle fibers gastrocnemius (type I, type IIa, type IIb), extensor digitorum longus muscle, and tibialis anterior muscle
- Training was performed using a treadmill (MK-680; manufactured by Muromachi Kikai Co., Ltd.) using an aging-accelerated model mouse (SAMP10 28 weeks old), and subsequent SV peptide administration was performed according to the schedule in the table below. After 30 weeks of age, training was continued from Monday to Friday of each week.
- the SV peptide was added to PBS to a concentration of 1 ⁇ g / ml to adjust the injection and was administered locally to the bilateral lower limb muscles of each mouse inhaled and anesthetized with sevoflurane immediately after training on Tuesday and Friday (SV). Group; administered twice a week).
- Exercise assessments were performed every other Friday.
- the exercise evaluation was an endurance evaluation in which the belt speed of the red mill was gradually increased at regular intervals.
- the elapsed time and the increase in belt speed adopted in the endurance evaluation test were the same conditions as in Example 4.
- the PBS group as in the SV group, after training with a treadmill, PBS was locally injected into the bilateral lower limb muscles instead of the SV peptide.
- the results of the endurance evaluation test are shown in FIG. 7 as a graph showing the difference between the average mileage on the reference date (30 weeks old) and the average mileage in each test.
- the average mileage increased from the reference date in the test at the age of 31 to 41 weeks.
- the SV group was able to suppress the decrease in average mileage during the test period compared to the PBS group.
- the average mileage decreased over time without exceeding the average mileage on the reference date during the test period.
- the results of the endurance evaluation test are shown in Fig. 8 as a graph showing the difference between the average speed on the reference date and the average speed on each test day.
- the average speed of each group was calculated as the average value of the maximum speed reached for each mouse belonging to each group (hereinafter, the average speed was calculated in the same manner).
- the mean rate continued to increase in the tests from 31 to 39 weeks of age.
- the SV group was able to suppress the decrease in average velocity during the test period compared to the PBS group.
- the average speed decreased significantly compared to the average speed on the reference day.
- FIG. 9 shows the average cross-sectional area of muscle fibers in each muscle of SV group and PBS group mice.
- the average cross-sectional area of muscle fibers was measured for each type of muscle fiber of the gastrocnemius muscle (type I, type IIa, type IIb).
- the average cross-sectional area of muscle fibers was calculated by measuring 50 or more muscle fiber types.
- the muscle fiber cross-sectional area was increased in all of type I, type IIa, and type IIb as compared with the PBS group (Figs. 10 and 11).
- Example 6 In this example, the frequency and dose of SV peptide in Example 4 were changed as shown in the table below, and exercise evaluation (endurance evaluation) was performed when SV peptide was continuously administered to the aging-accelerated model mice. .. Conditions other than the number and dose of SV peptide administration were the same as in Example 4. Specifically, SV peptide was added to PBS to a concentration of 2 ⁇ g / ml to adjust the injection, and immediately after training every other Friday (even week), both sides of each mouse inhaled with sevoflurane. Local injection was performed on the lower limb muscle (SV group; administered once every other week).
- FIG. 13 shows a graph showing the difference between the average mileage on the reference date (30 weeks old) and the average mileage in each test. As shown in Figures 12 and 13, the average mileage gradually decreased in the PBS group, while the average mileage increased significantly in the SV group from 31 weeks to 48 weeks. In addition, the SV group was able to maintain the same average mileage as the 30-week-old even after 49 weeks of age.
- Example 7 In this example, the frequency and dose of SV peptide in Example 4 were changed as shown in the table below, and exercise evaluation (endurance evaluation) was performed when SV peptide was continuously administered to the aging-accelerated model mice. .. Conditions other than the number and dose of SV peptide administration were the same as in Example 4. Specifically, SV peptide was added to PBS to a concentration of 20 ⁇ g / ml to adjust the injection, and both lower limbs of each mouse inhaled with sevoflurane immediately after training once every 4 weeks (Friday). Locally injected into the muscle (SV group; administered once every 4 weeks).
- FIG. 17 the change over time of the maximum speed average in each group is shown in FIG. 17, and the graphs showing the difference between the maximum speed average on the reference date and the maximum speed average on each test day are shown in FIGS. 18 and 19.
- the mean rate increased continuously in the test at 31 to 36 weeks of age.
- the SV group showed the same maximum speed average at 41 weeks of age as at 30 weeks of age.
- the average maximum speed decreased over time compared to the average speed on the reference date.
- the decrease in average velocity during the test period could be suppressed compared to the PBS group.
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Abstract
Description
筋損傷等により筋衛生細胞が活性化されると細胞増殖および筋芽細胞への分化が起こる。元々、筋衛星細胞は多分化能を有するが、活性化しMyoD遺伝子を発現することで、筋芽細胞への分化が決定付けられる。筋芽細胞は筋再生に必要な細胞数を確保するために増殖を繰り返す。また同時に下流遺伝子であるMyogenin遺伝子の発現が誘導され、そのMyogenin遺伝子は筋芽細胞の筋管細胞への分化・維持に関わり、成熟した筋細胞が形成される。筋細胞は筋線維と細胞融合することにより筋組織の再生を促す。ここで一部の筋芽細胞は再び細胞周期の静止期に入り、筋衛生細胞に戻ることで骨格筋に内在する筋衛生細胞数が制御されると考えられている。
しかしながら、筋衛生細胞は加齢に伴う細胞自身の内因性変化や増殖因子の減少などの外因性の変化により、細胞数の減少および自己複製能が低下すると考えられている。これによる筋再生能の低下がサルコペニア発症の要因の一つと考えられる。
本発明者らは、老化促進モデルマウスに対してSVペプチドを下肢の筋肉に局注することで、老化にともなう筋機能低下を抑制または改善できることを確認した。本発明は当該知見により完成された発明であり、以下の態様を含む:
本発明は一態様において、
〔1〕老化による骨格筋の機能低下を抑制または改善するための筋機能改善剤であって、
以下の(1)~(3)から選択される少なくとも一種のペプチドまたはその塩を有効成分として含有する筋機能改善剤に関する:
(1)配列番号1に示されるアミノ酸配列からなるペプチド、および、
(2)ヒトオステオポンチンのフラグメントであって、C末端のアミノ酸配列が配列番号1に示されるアミノ酸配列であるペプチド、ならびに、
(3)前記(1)または(2)におけるペプチドのアミノ酸配列において、1~数個のアミノ酸が欠失、置換もしくは付加されたアミノ酸配列からなり、かつ、老化に伴う骨格筋内の筋衛生細胞数の減少を抑制または改善する作用を有するペプチド。
また、本発明の筋機能改善剤は一実施の形態において、
〔2〕上記〔1〕に記載の筋機能改善剤であって、
前記(1)におけるペプチドのアミノ酸配列において、1~数個のアミノ酸が置換、付加、欠失したアミノ酸配列からなり、かつ、老化による骨格筋の機能低下を抑制または改善する作用を有するペプチドが下記(I)~(IV)のいずれかのアミノ酸配列からなるペプチドであり、
前記(2)におけるペプチドのアミノ酸配列において、1~数個のアミノ酸が置換、付加、欠失したアミノ酸配列からなり、かつ、老化による骨格筋の機能低下を抑制または改善する作用を有するペプチドが、ヒトオステオポンチンのフラグメントであって、前記フラグメントのC末端のアミノ酸配列が下記(I)~(IV)のいずれかのアミノ酸配列からなるペプチドであることを特徴とする。
X1-X2-Val-(Tyr/Phe/Trp)-X5-X6-X7 (I)
(式中X1、X2、X5、X6、およびX7は、同一または異なって任意のアミノ酸残基を表す。)
X1-X2-Val-(Tyr/Phe/Trp)-X5-X6 (II)
(式中X1、X2、X5およびX6は、同一または異なって任意のアミノ酸残基を表す。)
X2-Val-(Tyr/Phe/Trp)-X5-X6-X7 (III)
(式中X2、X5、X6およびX7は、同一または異なって任意のアミノ酸残基を表す。)
X1-X2-Val-(Tyr/Phe/Trp)-X5-X6-X7-X8 (IV)
(式中X1、X2、X5、X6、X7およびX8は、同一または異なって任意のアミノ酸残基を表す。)
また、本発明は別の態様において、
〔3〕老化による速筋繊維および/または遅筋繊維の筋委縮を抑制または改善するための、筋萎縮抑制剤であって、
以下の(1)~(3)から選択される少なくとも一種のペプチドまたはその塩を有効成分として含有する筋萎縮抑制剤:
(1)配列番号1に示されるアミノ酸配列からなるペプチド、および、
(2)ヒトオステオポンチンのフラグメントであって、C末端のアミノ酸配列が配列番号1に示されるアミノ酸配列であるペプチド、ならびに、
(3)前記(1)または(2)におけるペプチドのアミノ酸配列において、1~数個のアミノ酸が欠失、置換もしくは付加されたアミノ酸配列からなり、かつ、老化による速筋繊維および/または遅筋繊維の筋委縮を抑制または改善する作用を有するペプチドに関する。
ここで、本発明の筋萎縮抑制剤は一実施の形態において、
〔4〕上記〔3〕に記載の筋委縮抑制剤であって、
前記(1)におけるペプチドのアミノ酸配列において、1~数個のアミノ酸が置換、付加、欠失したアミノ酸配列からなり、かつ、老化による速筋繊維および/または遅筋繊維の筋委縮を抑制または改善する作用を有するペプチドが下記(I)~(IV)のいずれかのアミノ酸配列からなるペプチドであり、
前記(2)におけるペプチドのアミノ酸配列において、1~数個のアミノ酸が置換、付加、欠失したアミノ酸配列からなり、かつ、老化による速筋繊維および/または遅筋繊維の筋委縮を抑制または改善する作用を有するペプチドが、ヒトオステオポンチンのフラグメントであって、前記フラグメントのC末端のアミノ酸配列が下記(I)~(IV)のいずれかのアミノ酸配列からなるペプチドである、筋萎縮抑制剤。
X1-X2-Val-(Tyr/Phe/Trp)-X5-X6-X7 (I)
(式中X1、X2、X5、X6、およびX7は、同一または異なって任意のアミノ酸残基を表す。)
X1-X2-Val-(Tyr/Phe/Trp)-X5-X6 (II)
(式中X1、X2、X5およびX6は、同一または異なって任意のアミノ酸残基を表す。)
X2-Val-(Tyr/Phe/Trp)-X5-X6-X7 (III)
(式中X2、X5、X6およびX7は、同一または異なって任意のアミノ酸残基を表す。)
X1-X2-Val-(Tyr/Phe/Trp)-X5-X6-X7-X8 (IV)
(式中X1、X2、X5、X6、X7およびX8は、同一または異なって任意のアミノ酸残基を表す。)
また、本発明の筋機能改善剤は一実施の形態において、
〔5〕上記〔1〕または〔2〕に記載の筋機能改善剤であって、
前記骨格筋への刺激の負荷と併用するための筋機能改善剤であることを特徴とする。
また、本発明の筋機能改善剤は一実施の形態において、
〔6〕上記〔5〕に記載の筋機能改善剤であって、
サルコペニアまたは封入体筋炎による骨格筋の機能低下を予防または改善するための筋機能改善剤であることを特徴とする。
また、本発明の筋機能改善剤は一実施の形態において、
〔7〕上記〔6〕に記載の筋機能改善剤であって、
前記骨格筋への刺激の負荷が運動療法であることを特徴とする。
また、本発明の筋機能改善剤は一実施の形態において、
〔8〕骨格筋の機能低下を抑制または改善するための筋機能改善剤であって、
前記筋機能改善剤は刺激の負荷と併用するものであり、かつ、
以下の(1)~(3)から選択される少なくとも一種のペプチドまたはその塩を有効成分として含有する筋機能改善剤:
(1)配列番号1に示されるアミノ酸配列からなるペプチド、および、
(2)ヒトオステオポンチンのフラグメントであって、C末端のアミノ酸配列が配列番号1に示されるアミノ酸配列であるペプチド、ならびに、
(3)前記(1)または(2)におけるペプチドのアミノ酸配列において、1~数個のアミノ酸が欠失、置換もしくは付加されたアミノ酸配列からなり、かつ、骨格筋の機能低下を抑制または改善する作用を有するペプチド。
以下の(1)~(3)から選択される少なくとも一種のペプチドまたはその塩を有効成分として含有する筋機能改善剤を提供する:
(1)配列番号1に示されるアミノ酸配列からなるペプチド、および、
(2)ヒトオステオポンチンのフラグメントであって、C末端のアミノ酸配列が配列番号1に示されるアミノ酸配列であるペプチド、ならびに、
(3)前記(1)または(2)におけるペプチドのアミノ酸配列において、1~数個のアミノ酸が置換、付加、欠失したアミノ酸配列からなり、かつ、老化に伴う老化による骨格筋の機能低下を抑制または改善する作用を有するペプチド。
なお保存的置換として特定のアミノ酸に対して機能的に類似のアミノ酸は当技術分野において周知である。アミノ酸側鎖の特性の例は、疎水性アミノ酸(A、I、L、M、F、P、W、Y、V)、親水性アミノ酸(R、D、N、C、E、Q、G、H、K、S、T)、および以下の共通する官能基または特徴を有する側鎖:脂肪族側鎖(G、A、V、L、I、P);ヒドロキシル基含有側鎖(S、T、Y);硫黄原子含有側鎖(C、M);カルボン酸およびアミド含有側鎖(D、N、E、Q);塩基含有側鎖(R、K、H);ならびに芳香族含有側鎖(H、F、Y、W)である。また以下の8群は各々相互に保存的置換であるアミノ酸を含む:1)アラニン(A)、グリシン(G);2)アスパラギン酸(D)、グルタミン酸(E);3)アスパラギン(N)、グルタミン(Q);4)アルギニン(R)、リシン(K);5)イソロイシン(I)、ロイシン(L)、メチオニン(M)、バリン(V);6)フェニルアラニン(F)、チロシン(Y)、トリプトファン(W);7)セリン(S)、トレオニン(T);および8)システイン(C)、メチオニン(M)(例えばCreighton,Proteins 1984参照)。
X1-X2-Val-(Tyr/Phe/Trp)-X5-X6-X7 (I)
(式中X1、X2、X5、X6、およびX7は、同一または異なって任意のアミノ酸残基を表す。)
X1-X2-Val-(Tyr/Phe/Trp)-X5-X6 (II)
(式中X1、X2、X5およびX6は、同一または異なって任意のアミノ酸残基を表す。)
X2-Val-(Tyr/Phe/Trp)-X5-X6-X7 (III)
(式中X2、X5、X6およびX7は、同一または異なって任意のアミノ酸残基を表す。)
X1-X2-Val-(Tyr/Phe/Trp)-X5-X6-X7-X8 (IV)
(式中X1、X2、X5、X6、X7およびX8は、同一または異なって任意のアミノ酸残基を表す。)
なお、好ましい実施の形態において、上記(I)~(IV)のいずれかのアミノ酸配列中のX1はセリンまたはその保存的置換アミノ酸であり、X2およびX3はバリンまたはその保存的置換アミノ酸であり、X5はグリシンまたはその保存的置換アミノ酸であり、X6はロイシンまたはその保存的置換アミノ酸であり、または、X7はアルギニンまたはその保存的置換アミノ酸である。
また上記(I)~(IV)のいずれかのアミノ酸配列からなるペプチドは、老化による骨格筋の機能低下を抑制または改善する作用を有する限りにおいて、そのN末端またはC末端にさらに数個のアミノ酸を有していても良い。
X1-Val-Val-(Tyr/Phe/Trp)-X5-X6-X7 (V)
サルコペニアとは、加齢などにより骨格筋量の低下と筋力もしくは身体機能の低下により定義される。サルコペニアの判定基準は複数報告があり、例えば、サルコペニア診療ガイドライン2017年版(発行元:日本サルコペニア・フレイル学会 国立長寿医療研究センター)などにまとめられている。またサルコペニアには、加齢に伴う一次性サルコペニアと加齢以外の原因に伴う二次サルコペニア(活動不足などの活動に関連して生じるサルコペニア、臓器不全、炎症性疾患、悪性腫瘍、内分泌疾患などの疾患に関連して生じるサルコペニア、栄養不足などの栄養に関連して生じるサルコペニアを含む)とに分類されている。本発明の筋機能改善剤は一次性サルコペニアおよび二次サルコペニアのいずれも治療対象とすることができる。
骨格筋の筋委縮の具体例としては、以下に限定されないが、下肢筋委縮、下肢筋廃用委縮、筋委縮症、肩甲上腕筋委縮、四肢筋委縮、上肢筋委縮、全身性筋萎縮、僧帽筋部筋委縮、退行性筋萎縮、廃用症候群、廃用性筋委縮、母指球筋委縮などを挙げることができる。
投与量は、機能低下部位、投与ルートなどにより差異はあるが、例えば、成人の機能低下した骨格筋の周囲の筋肉内に注射する場合、有効成分の1日当たりの投与量は、約0.00001~100mgであってもよく、約0.00002~90mgであってもよく、約0.00005~80mgであってもよく、約0.0001~50mgであってもよく、約0.01~30mgであってもよく、約0.1~20mgであってもよく、約0.1~10mgであってもよい。
本発明の筋機能改善剤は、例えば毎日(1日あたり1回、1日あたり2回、1日あたり3回、1日あたり4回、1日あたり5回、1日あたり6回)、2日毎に1回、3日毎に1回、4日毎に1回、5日毎に1回、6日毎に1回、毎週、1週間に2回、隔週、3週間毎に1回、4週間に1回、毎月1回、2ヶ月に1回、3ヶ月に1回、4ヶ月に1回、5ヶ月に1回または6ヶ月に1回投与することができる。
本発明に係る筋機能改善剤は骨格筋への刺激の負荷と併用することで、筋機能改善剤単独で用いた場合もしくは骨格筋への刺激負荷単独と比較してより骨格筋の機能低下を抑制することができる。また好ましい実施の形態において本発明に係る筋機能改善剤は、筋機能改善剤単独で用いた場合もしくは骨格筋への刺激負荷単独においては得ることのできない優れた筋機能改善効果を奏することができる。
「骨格筋への刺激の負荷」は骨格筋の筋収縮および/または筋弛緩を惹起する刺激の負荷であれば限定されない。骨格筋への刺激の負荷としては、公知の刺激負荷方法を採用することができる。以下に限定されないが、運動療法などによる刺激の負荷、生理学的筋刺激法(例えば電気刺激法(神経筋電気刺激法:NMES)(Jpn J Rehabil Med 2017;54:764-767)による負荷、振動による刺激負荷(例えば、特許6886559号公報参照)などを挙げることができる。
「機能低下した骨格筋への運動負荷」は、本発明の筋機能改善剤と併用した際に骨格筋の機能低下を抑制または改善できる限りにおいて限定されず、以下に限定されないが、例えばサルコペニアに罹患した患者を対象とする場合、サルコペニアの治療に用いられる公知の運動療法を採用することができる。対象の年齢や健康状態、対象とする骨格筋や骨格筋量に応じて適宜好ましい運動負荷方法を設定することができる。
運動負荷方法の具体例としては、大腿四頭筋が対象のときスクワット、膝伸ばし、膝上げなどを挙げることができ、中殿筋が対象のとき片脚立ち運動などを挙げることができ、腓腹筋が対象のときかかと上げ運動などを挙げることができる。上記は一例にすぎず、当業者であれば対象とする骨格筋に応じて適切な運動負荷方法を採用し、その回数やセット数を設定することができる。
「骨格筋への生理学的筋刺激法による負荷」や「骨格筋への振動による刺激負荷」は本発明の筋機能改善剤と併用した際に骨格筋の機能低下を抑制または改善できる限りにおいて限定されず、通常臨床において用いられる公知の刺激付与手段や方法を採用することができる。当業者であれば対象の年齢や健康状態、対象とする骨格筋や骨格筋量に応じて適宜好ましい刺激負荷方法を設定することができる。
「機能低下した骨格筋への刺激の負荷」は、老化による骨格筋の機能低下を抑制または改善できる限りにおいて本発明の筋機能改善剤の投与前(例えば、30分前、1時間前、2時間前、6時間前、12時間前、1日前など)、投与時、投与後(例えば、30分後、1時間後、2時間後、6時間後、12時間後、1日後など)のいずれの時点において行ってもよい。好ましくは、骨格筋への刺激負荷後または刺激負荷と同時に、本発明の筋機能改善剤を投与する実施形態である。
(1)配列番号1に示されるアミノ酸配列からなるペプチド、および、
(2)ヒトオステオポンチンのフラグメントであって、C末端のアミノ酸配列が配列番号1に示されるアミノ酸配列であるペプチド、ならびに、
(3)前記(1)または(2)におけるペプチドのアミノ酸配列において、1~数個のアミノ酸が欠失、置換もしくは付加されたアミノ酸配列からなり、かつ、骨格筋の機能低下を抑制または改善する作用を有するペプチド。
本態様において、本発明の筋機能改善剤は骨格筋への刺激負荷と併用することにより、老化により機能が低下した骨格筋に加えて、例えば、筋断裂、筋委縮、筋変性等の骨格筋の損傷を修復する、または、当該損傷により低下した骨格筋の機能を改善する。骨格筋の損傷としては、例えば、筋断裂、筋委縮、筋変性等が挙げられる。具体的には、大きな外傷に伴う筋断裂、外科手術に伴う筋断裂、骨折・打撲・肉離れ等の外傷に伴う筋断裂、アスリートの筋肉損傷、靭帯の術後の筋断裂または筋委縮、人工股関節手術後の筋断裂または筋委縮、長期閉口状態を要する頭頸部手術後の運動単位減少による廃用性筋萎縮、がん悪液質に伴う筋萎縮、筋ジストロフィー症等の遺伝性神経筋疾患における進行性筋萎縮、脊柱起立筋障害に伴う筋委縮、腰椎椎間板ヘルニアに伴う筋委縮、首下がり症候群に伴う筋委縮、封入体筋炎、広範囲筋切除を伴う外科手術後の線維化・瘢痕拘縮、口蓋裂等の先天性筋形態異常に対する形成手術後の運動機能不全を伴う瘢痕拘縮などが挙げられる。例えば、外科手術後のリハビリテーションなどの運動負荷と併用して筋機能改善剤を用いることができる。
以下の(1)~(3)から選択される少なくとも一種のペプチドまたはその塩を有効成分として含有する筋繊維肥大促進剤を含む:
(1)配列番号1に示されるアミノ酸配列からなるペプチド、および、
(2)ヒトオステオポンチンのフラグメントであって、C末端のアミノ酸配列が配列番号1に示されるアミノ酸配列であるペプチド、ならびに、
(3)前記(1)または(2)におけるペプチドのアミノ酸配列において、1~数個のアミノ酸が欠失、置換もしくは付加されたアミノ酸配列からなり、かつ、老化に伴う骨格筋内の筋衛生細胞数の減少を抑制または改善する作用を有するペプチド。
また本発明は別の態様として、老化による骨格筋の筋再生能の低下を改善するための筋再生能改善剤であって、上記(1)~(3)から選択される少なくとも一種のペプチドまたはその塩を含む筋再生能改善剤を提供する。
本発明の筋繊維肥大促進剤および筋再生能改善剤は、上記本発明の筋機能改善剤の実施の形態と同様に実施することができる。
(a1)上記(1)~(3)から選択される少なくとも一種のペプチドまたはその塩の治療有効量を老化により機能低下した骨格筋を有する対象に投与することを特徴とする、老化による骨格筋の機能低下改善方法。
(a1’)上記(a1)に記載の老化による骨格筋の機能低下改善方法であって、前記老化により機能低下した骨格筋またはその周囲の骨格筋に刺激負荷を加える工程をさらに含むことを特徴とする、老化による骨格筋の機能低下改善方法。
(a1’’)上記(a1)に記載の老化による骨格筋の機能低下改善方法であって、前記ペプチドまたはその塩を投与が、前記老化により機能低下した骨格筋またはその周囲の骨格筋へ投与であることを特徴とする、老化による骨格筋の機能低下改善方法。
(a2)上記(1)~(3)から選択される少なくとも一種のペプチドまたはその塩の治療有効量を老化により萎縮した速筋繊維および/または遅筋繊維を有する対象に投与することを特徴とする、老化により萎縮した速筋繊維および/または遅筋繊維の肥大方法。
(a2’)上記(a2)に記載の老化により萎縮した速筋繊維および/または遅筋繊維の肥大方法であって、前記投与が骨格筋への刺激の負荷との併用であることを特徴とする、老化による骨格筋の機能低下改善方法。
(b1)老化による骨格筋の機能低下改善に使用するための、上記(1)~(3)から選択される少なくとも一種のペプチドまたはその塩。
(b2)老化により萎縮した速筋繊維および/または遅筋繊維の肥大に使用するための、上記(1)~(3)から選択される少なくとも一種のペプチドまたはその塩。
(c1)老化による骨格筋の機能低下を抑制または改善させる筋機能改善剤を製造するための、上記(1)~(3)から選択される少なくとも一種のペプチドまたはその塩の使用。
(c2)老化により萎縮した速筋繊維および/または遅筋繊維を肥大させる筋繊維肥大促進剤を製造するための、上記(1)~(3)から選択される少なくとも一種のペプチドまたはその塩の使用。
(c1’)上記(b1)に記載のペプチドまたはその塩であって、前記ペプチドまたはその塩は骨格筋への刺激の負荷と併用するものであることを特徴とする。
本実施例では、老化促進モデルマウスにSVVYGLRのアミノ酸配列(配列番号1)からなるペプチド(SVペプチド)を投与し、筋機能回復作用について確認した。
被験ペプチドとして用いたSVペプチドは、多種品目固相法自動ペプチド合成装置(PSSM-8; 島津製作所)を用いてFmoc法により合成した。SVペプチドをPBSに添加し、20ng/mlとなるように調整して注射剤を作製した。
老化促進モデルマウス(SAMP10 21週齢)を用いてトレッドミル(MK-680; 室町機械株式会社製)を用いたトレーニングの施行とその後のSVペプチド投与を下記表のスケジュールに沿って行った。
週1回、マウスに対してトレッドミルを用いた衝突回数測定試験を行った。SVペプチド局注後、再度トレッドミル(18 m/min ×90min)を施行し、トレッドミル施行時に老化促進モデルマウスがベルトの速度と同等以上の速度で走ることができずにトレッドミルの壁に衝突した回数を測定した。トレッドミルによるトレーニング施行、ペプチドの局注、および、週1回の衝突回数測定を老化促進モデルマウスが35週齢になるまで継続した。また対照群では、実験群と同様にトレッドミルによるトレーニングを施行後、SVペプチドの代わりにPBSを両側下肢筋に局注し、週1回衝突回数測定を行った。
その結果、30週齢以降で対照群では経時的に衝突回数は増加傾向を示したものの、実験群においては、対照群と比較して有意に衝突回数増加を抑制する効果が得られた(図1)。この結果より、SVペプチドの投与が老化促進モデルマウスの下肢の筋機能の回復を促したことが推察される。
本実施例では、老化促進モデルマウスにSVペプチドを投与し、投与から一定時間経過後の筋機能回復作用について確認した。
老化促進モデルマウス(SAMP10 36週齢)を用いてトレッドミルによるトレーニングを実施例1の35週齢マウスの本トレーニングと同様の条件で施行し、トレッドミル施行後すぐにSVペプチド(total 40ng)を両側下肢筋に局注した(実験群)。SVペプチド投与も実施例1の35週齢マウスと同様の投与部位、投与量で行った。局注から12時間後、24時間後、または72時間後にトレッドミルによるトレーニング(18 m/min ×90min)を再試行して衝突回数を評価した。また対照群では、実験群と同様にトレッドミルによるトレーニングを施行後、SVペプチドの代わりにPBSを両側下肢筋に局注し、局注から12時間後、24時間後、または72時間後にトレッドミルによる衝突回数測定を行った。
その結果、実験群では対照群と比較して、局注後12時間、24時間、72時間における衝突回数が有意に減少した。この結果よりSVペプチド投与が運動後の筋機能回復を促進したことが推察される(図2)。
本実施例では、老化促進モデルマウスに継続的にSVペプチドを投与した際の筋繊維を評価した。
老化促進モデルマウス(SAMP10 21週齢)を用いてトレッドミル(MK-680; 室町機械株式会社製)(18 m/min ×90min)を用いたトレーニングの施行とその後のSVペプチド投与を実施例1と同様のスケジュールに沿って行った。なお、36週齢以降は35週齢と同様の条件でトレッドミルを用いたトレーニングの施行とその後のSVペプチド投与を行い、老化促進モデルマウスが40週齢になるまで継続した。対照群では、実験群と同様の条件にてトレーニングを施行後、SVペプチドの代わりにPBSを両側下肢筋に局注した。
その後、40週齢の老化促進モデルマウスから下肢の腓腹筋およびヒラメ筋を摘出し、定法に従い切片を作製後、HE染色を行った。図3Aは筋繊維横断面の腓腹筋のHE染色画像を示す。また図3Bは、ヒラメ筋における遅筋と同定した筋繊維の平均横断面積と、腓腹筋における速筋と同定した筋繊維の平均横断面積を示す。SV投与群では、速筋、遅筋ともに筋繊維平均横断面積は対照群と比較して有意に高値を示した(図3B)。
本実施例では、老化促進モデルマウスに継続的にSVペプチドを投与した際の運動評価を行った。
老化促進モデルマウス(SAMP10 28週齢)を用いてトレッドミル(MK-680; 室町機械株式会社製)を用いたトレーニングの施行とその後のSVペプチド投与を下記表のスケジュールに沿って行った。30週齢以降は、各週の月曜日から金曜日まで連続してトレーニングを行った。SVペプチドは、1μg/mlまたは20ng/mlの濃度となるようにPBSに添加して注射剤を調整し、火曜日および金曜日のトレーニング後すぐに、セボフルランで吸入麻酔した各マウスの両側下肢筋に局注した(SV群)。運動評価は、金曜日のSVペプチド局注後に行った。
運動評価は、レッドミルのベルトスピードを一定時間ごと段階的に上昇させる持久力評価と、ベルトの傾斜を一定時間ごと段階的に上昇させるスロープアップ評価を行った。運動評価試験に採用した経過時間とベルトスピードまたはベルトの傾斜の上昇の関係を図4に示す。また対照群であるPBS群では、SV群と同様にトレッドミルによるトレーニングを施行後、SVペプチドの代わりにPBSを両側下肢筋に局注した。
スロープアップ評価試験の結果を平均仕事量の変化率のグラフとして図6に示す。平均仕事量は、各群に属するマウスごとの仕事量を体重、走行時間、傾斜(grade)、走行速度、および重力加速度g(9.8m/s2)を乗じて算出し、その平均値として算出した。図6に示すように、SV投与群は、PBS群に対してより高い仕事量を示した。
本実施例では、実施例4に対してトレーニング内容およびSVペプチド投与濃度を変更し、老化促進モデルマウスに継続的にSVペプチドを投与した際の運動評価(持久力評価)を行った。また、51週齢までトレーニングおよびSVペプチド投与を継続したマウスの筋繊維(腓腹筋(type I、type IIa、type IIb)、長趾伸筋、および、前脛骨筋)横断面積を評価した。
老化促進モデルマウス(SAMP10 28週齢)を用いてトレッドミル(MK-680; 室町機械株式会社製)を用いたトレーニングの施行とその後のSVペプチド投与を下記表のスケジュールに沿って行った。30週齢以降は、各週の月曜日から金曜日まで連続してトレーニングを行った。SVペプチドは、1μg/mlの濃度となるようにPBSに添加して注射剤を調整し、火曜日および金曜日のトレーニング後すぐに、セボフルランで吸入麻酔した各マウスの両側下肢筋に局注した(SV群;週2回投与)。運動評価は、隔週の金曜日毎に行った。
運動評価は、レッドミルのベルトスピードを一定時間ごと段階的に上昇させる持久力評価を行った。持久力評価試験に採用した経過時間とベルトスピードの上昇は実施例4と同様の条件とした。また対照群であるPBS群では、SV群と同様にトレッドミルによるトレーニングを施行後、SVペプチドの代わりにPBSを両側下肢筋に局注した。
本実施例では、実施例4のSVペプチド投与回数および投与量を下記表のように変更し、老化促進モデルマウスに継続的にSVペプチドを投与した際の運動評価(持久力評価)を行った。SVペプチド投与回数および投与量以外の条件は実施例4と同一とした。
具体的には、SVペプチドを2μg/mlの濃度となるようにPBSに添加して注射剤を調整し、隔週(偶数週)の金曜日のトレーニング後すぐに、セボフルランで吸入麻酔した各マウスの両側下肢筋に局注した(SV群;隔週1回投与)。
本実施例では、実施例4のSVペプチド投与回数および投与量を下記表のように変更し、老化促進モデルマウスに継続的にSVペプチドを投与した際の運動評価(持久力評価)を行った。SVペプチド投与回数および投与量以外の条件は実施例4と同一とした。
具体的には、SVペプチドを20μg/mlの濃度となるようにPBSに添加して注射剤を調整し、4週に一度(金曜日)トレーニング後すぐに、セボフルランで吸入麻酔した各マウスの両側下肢筋に局注した(SV群;4週1回投与)。
Claims (8)
- 老化による骨格筋の機能低下を抑制または改善するための筋機能改善剤であって、
以下の(1)~(3)から選択される少なくとも一種のペプチドまたはその塩を有効成分として含有する筋機能改善剤:
(1)配列番号1に示されるアミノ酸配列からなるペプチド、および、
(2)ヒトオステオポンチンのフラグメントであって、C末端のアミノ酸配列が配列番号1に示されるアミノ酸配列であるペプチド、ならびに、
(3)前記(1)または(2)におけるペプチドのアミノ酸配列において、1~数個のアミノ酸が欠失、置換もしくは付加されたアミノ酸配列からなり、かつ、老化による骨格筋の機能低下を抑制または改善する作用を有するペプチド。 - 請求項1に記載の筋機能改善剤であって、
前記(1)におけるペプチドのアミノ酸配列において、1~数個のアミノ酸が置換、付加、欠失したアミノ酸配列からなり、かつ、老化による骨格筋の機能低下を抑制または改善する作用を有するペプチドが下記(I)~(IV)のいずれかのアミノ酸配列からなるペプチドであり、
前記(2)におけるペプチドのアミノ酸配列において、1~数個のアミノ酸が置換、付加、欠失したアミノ酸配列からなり、かつ、老化による骨格筋の機能低下を抑制または改善する作用を有するペプチドが、ヒトオステオポンチンのフラグメントであって、前記フラグメントのC末端のアミノ酸配列が下記(I)~(IV)のいずれかのアミノ酸配列からなるペプチドである、筋機能改善剤。
X1-X2-Val-(Tyr/Phe/Trp)-X5-X6-X7 (I)
(式中X1、X2、X5、X6、およびX7は、同一または異なって任意のアミノ酸残基を表す。)
X1-X2-Val-(Tyr/Phe/Trp)-X5-X6 (II)
(式中X1、X2、X5およびX6は、同一または異なって任意のアミノ酸残基を表す。)
X2-Val-(Tyr/Phe/Trp)-X5-X6-X7 (III)
(式中X2、X5、X6およびX7は、同一または異なって任意のアミノ酸残基を表す。)
X1-X2-Val-(Tyr/Phe/Trp)-X5-X6-X7-X8 (IV)
(式中X1、X2、X5、X6、X7およびX8は、同一または異なって任意のアミノ酸残基を表す。) - 老化による速筋繊維および/または遅筋繊維の筋委縮を抑制または改善するための、筋萎縮抑制剤であって、
以下の(1)~(3)から選択される少なくとも一種のペプチドまたはその塩を有効成分として含有する筋萎縮抑制剤剤:
(1)配列番号1に示されるアミノ酸配列からなるペプチド、および、
(2)ヒトオステオポンチンのフラグメントであって、C末端のアミノ酸配列が配列番号1に示されるアミノ酸配列であるペプチド、ならびに、
(3)前記(1)または(2)におけるペプチドのアミノ酸配列において、1~数個のアミノ酸が欠失、置換もしくは付加されたアミノ酸配列からなり、かつ、老化による速筋繊維および/または遅筋繊維の筋委縮を抑制または改善する作用を有するペプチド。 - 請求項3に記載の筋萎縮抑制剤であって、
前記(1)におけるペプチドのアミノ酸配列において、1~数個のアミノ酸が置換、付加、欠失したアミノ酸配列からなり、かつ、老化による速筋繊維および/または遅筋繊維の筋委縮を抑制または改善する作用を有するペプチドが下記(I)~(IV)のいずれかのアミノ酸配列からなるペプチドであり、
前記(2)におけるペプチドのアミノ酸配列において、1~数個のアミノ酸が置換、付加、欠失したアミノ酸配列からなり、かつ、老化による速筋繊維および/または遅筋繊維の筋委縮を抑制または改善する作用を有するペプチドが、ヒトオステオポンチンのフラグメントであって、前記フラグメントのC末端のアミノ酸配列が下記(I)~(IV)のいずれかのアミノ酸配列からなるペプチドである、筋萎縮抑制剤。
X1-X2-Val-(Tyr/Phe/Trp)-X5-X6-X7 (I)
(式中X1、X2、X5、X6、およびX7は、同一または異なって任意のアミノ酸残基を表す。)
X1-X2-Val-(Tyr/Phe/Trp)-X5-X6 (II)
(式中X1、X2、X5およびX6は、同一または異なって任意のアミノ酸残基を表す。)
X2-Val-(Tyr/Phe/Trp)-X5-X6-X7 (III)
(式中X2、X5、X6およびX7は、同一または異なって任意のアミノ酸残基を表す。)
X1-X2-Val-(Tyr/Phe/Trp)-X5-X6-X7-X8 (IV)
(式中X1、X2、X5、X6、X7およびX8は、同一または異なって任意のアミノ酸残基を表す。) - 請求項1または2に記載の筋機能改善剤であって、
前記骨格筋への刺激の負荷と併用するための筋機能改善剤。 - 請求項5に記載の筋機能改善剤であって、
サルコペニアまたは封入体筋炎による骨格筋の機能低下を予防または改善するための筋機能改善剤。 - 請求項6に記載の筋機能改善剤であって、
前記骨格筋への刺激の負荷が運動療法である、筋機能改善剤。 - 骨格筋の機能低下を抑制または改善するための筋機能改善剤であって、
前記筋機能改善剤は刺激の負荷と併用するものであり、かつ、
以下の(1)~(3)から選択される少なくとも一種のペプチドまたはその塩を有効成分として含有する筋機能改善剤:
(1)配列番号1に示されるアミノ酸配列からなるペプチド、および、
(2)ヒトオステオポンチンのフラグメントであって、C末端のアミノ酸配列が配列番号1に示されるアミノ酸配列であるペプチド、ならびに、
(3)前記(1)または(2)におけるペプチドのアミノ酸配列において、1~数個のアミノ酸が欠失、置換もしくは付加されたアミノ酸配列からなり、かつ、骨格筋の機能低下を抑制または改善する作用を有するペプチド。
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