JP2018527364A - Composition for promoting differentiation of muscle cells containing amino acid - Google Patents
Composition for promoting differentiation of muscle cells containing amino acid Download PDFInfo
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- JP2018527364A JP2018527364A JP2018513476A JP2018513476A JP2018527364A JP 2018527364 A JP2018527364 A JP 2018527364A JP 2018513476 A JP2018513476 A JP 2018513476A JP 2018513476 A JP2018513476 A JP 2018513476A JP 2018527364 A JP2018527364 A JP 2018527364A
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- differentiation
- muscle
- composition
- phenylalanine
- methionine
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Abstract
本発明はアミノ酸を含有する筋細胞分化促進用組成物に関し、より具体的には、フェニルアラニン及びメチオニンからなる筋細胞分化促進剤と、これを含有する老人性筋損失予防または治療用薬学組成物及び老人性筋損失予防または改善用健康機能食品組成物に関する。本発明の筋細胞分化促進用組成物及びこれを含む薬学組成物または健康機能食品組成物は、筋芽細胞が筋肉細胞に分化されることを促進して筋肉減少症や筋損失を予防、改善及び治療することができ、特に老人性筋損失に効果的であり、筋細胞数の増加により基礎代謝量が増加して体内脂肪酸を酸化させるという効果を奏する。【選択図】図1The present invention relates to a composition for promoting differentiation of muscle cells containing an amino acid, more specifically, a composition for promoting differentiation of muscle cells comprising phenylalanine and methionine, a pharmaceutical composition for preventing or treating senile muscle loss containing the same, and The present invention relates to a health functional food composition for preventing or improving senile muscle loss. The composition for promoting the differentiation of muscle cells of the present invention and the pharmaceutical composition or health functional food composition containing the composition promotes the differentiation of myoblasts into muscle cells to prevent or improve muscle loss or muscle loss. In particular, it is effective for senile muscle loss, and has the effect of increasing the basal metabolic rate due to the increase in the number of muscle cells and oxidizing fatty acids in the body. [Selection] Figure 1
Description
本発明はアミノ酸を含有する筋細胞分化促進用組成物に関し、より具体的には、フェニルアラニン及びメチオニンからなる筋細胞分化促進剤と、これを含有する老人性筋損失予防または治療用薬学組成物及び老人性筋損失予防または改善用健康機能食品組成物に関する。 The present invention relates to a composition for promoting differentiation of muscle cells containing an amino acid, more specifically, a composition for promoting differentiation of muscle cells comprising phenylalanine and methionine, a pharmaceutical composition for preventing or treating senile muscle loss containing the same, and The present invention relates to a health functional food composition for preventing or improving senile muscle loss.
我々の体の筋肉は骨に付いて骨を保護し、体形を正しく保持するなど様々な機能を果たす。また、筋肉はカルシウムの流入を促進して骨密度を高めたりする。しかし、体は老化しながら構成成分の変化で体脂肪と体タンパク質の再分布が発生し、約50歳になると筋細胞内のタンパク質の合成速度が分解速度より遅くなって筋肉が急激に退化を始めるようになって、筋肉減少疾患に露出される虞がある。 The muscles of our body perform various functions such as attaching to the bones to protect the bones and to maintain the body shape correctly. Muscles also promote calcium influx and increase bone density. However, as the body ages, redistribution of body fat and body protein occurs due to changes in the components, and at about 50 years of age, the protein synthesis rate in muscle cells is slower than the degradation rate, causing muscles to degenerate rapidly. As you begin, you may be exposed to muscle loss.
筋肉減少の疾患の一つである筋肉減少症は普段自分の体質量の約13〜24%が減少した状態を言い、筋肉減少症があれば行動量が格段と減って精神健康を損なうだけでなく、生活の満足度も下がって、簡単な日常生活でも容易に負傷を負い、深刻な重傷に至ったりする。 Muscle loss, one of the diseases of muscle loss, usually refers to a state in which about 13 to 24% of your body mass has been reduced, and if you have muscle loss, the amount of action will be greatly reduced and mental health will be impaired. In addition, the level of satisfaction with life is reduced, and even in simple daily life, it is easily injured, resulting in serious injuries.
筋肉減少症の原因は老化が進行するにつれて発生する骨格筋の量と質の漸進的減少及び不適切な食餌エネルギーの攝取による脂肪と体脂肪成分を含む体重減少などを原因として挙げることができ、よく老化によるもので、年齢との係わり合いが深い。それ故、老化による筋肉減少症または筋損失を防止するための研究が必要な実情である。 Causes of sarcopenia can be attributed to gradual decrease in the amount and quality of skeletal muscle that occurs as aging progresses and weight loss including fat and body fat components due to improper dietary energy capture, Often due to aging, deeply related to age. Therefore, there is a need for research to prevent muscle loss or muscle loss due to aging.
ロイシン(leucine)を含む分岐鎖アミノ酸(branched-chain amino acid)がmTOR(Mammalian Target of Rapamycin)信号伝逹を通じて筋肉細胞でタンパク質を合成するメカニズムを通じた筋肉強化効果は90年代末から報告されており、大きく二つの部分で研究方向が行われて来た。第一は、ある特定アミノ酸がmTORを通じた筋肉強化効果があるかに関する研究であり、これに対して個別アミノ酸を取り除いた状態で筋肉強化効果を測定した結果、分岐鎖アミノ酸が効果がよく、その中でもロイシン(leucine)が最も効果が優れるという報告があった。また、多くのアミノ酸の間のシナジー効果においては、グルタミン(glutamine)がロイシン(leucine)の細胞内の吸収を促進してmTOR信号伝逹を通じた筋肉強化効果が増加されるという報告があった。第二は、アミノ酸がどのように細胞内で認識されてmTOR信号伝逹を活性化させるかに関する研究であり、これに対して2000年代後半から報告され始めたが、Vps34、MAP4K3、Rag GTPaseが中間媒介体に提示されて来た。その後、本発明者はロイシン−tRNA合成酵素(leucyl-tRNA synthase)がロイシン(leucine)を直接認識してRag GTPaseを活性化させることによりmTORが活性化されるということを明かした事がある。 Muscle strengthening effects have been reported since the end of the 90s through a mechanism in which branched-chain amino acids containing leucine synthesize proteins in muscle cells through mTOR (Mammalian Target of Rapamycin) signaling. The research direction has been carried out in two major parts. The first is research on whether a specific amino acid has a muscle strengthening effect through mTOR. On the other hand, as a result of measuring the muscle strengthening effect with individual amino acids removed, branched-chain amino acids are effective. Among them, leucine was reported to be most effective. Moreover, in the synergy effect between many amino acids, it has been reported that glutamine promotes intracellular absorption of leucine and increases the muscle strengthening effect through mTOR signal transmission. The second is a study on how amino acids are recognized in cells to activate mTOR signaling. In contrast, Vps34, MAP4K3, and Rag GTPase have been reported since the late 2000s. It has been presented to intermediate mediators. Thereafter, the present inventor has revealed that mTOR is activated when leucine-tRNA synthase directly recognizes leucine and activates Rag GTPase.
しかしながら、mTOR信号伝逹関連機作は何れも筋肉内のタンパク質の合成を増加させることにより筋肉強化効果を現わすだけで、筋芽細胞を筋細胞に分化させて筋細胞の数自体を増加させることにより、減少されたり損失された筋肉量を根本的に回復させるメカニズムとは差がある。 However, all the mTOR signal transmission mechanisms only increase muscle synthesis by increasing the synthesis of protein in muscle, and differentiate myoblasts into muscle cells to increase the number of muscle cells themselves. This is different from the mechanism that fundamentally recovers the lost or lost muscle mass.
ここで、本発明者等は筋肉内タンパク質の合成ではない、筋細胞の分化形成を増加させるための方法を見つけるために鋭意努力した結果、アミノ酸の中でフェニルアラニン(phenylalanine)とメチオニン(methionine)が一緒に作用して筋芽細胞が筋肉細胞に分化されることを促進することにより老人性筋損失を予防したり、改善、治療することができることを確認して、本発明の完成に至った。 Here, as a result of diligent efforts to find a method for increasing the differentiation formation of muscle cells, which is not the synthesis of intramuscular proteins, the present inventors found that phenylalanine and methionine are among amino acids. It was confirmed that the loss of senile muscle can be prevented, improved or treated by acting together to promote the differentiation of myoblasts into muscle cells, and the present invention has been completed.
本発明の目的は、フェニルアラニン(Phe)及びメチオニン(Met)からなる筋細胞分化促進剤と、ここに薬剤学的または食品学的に許容される添加剤をさらに含有する筋細胞分化促進用組成物を提供することにある。 An object of the present invention is to provide a composition for promoting myocyte differentiation, further comprising a myocyte differentiation promoting agent comprising phenylalanine (Phe) and methionine (Met), and a pharmaceutically or food acceptable additive. Is to provide.
即ち、本発明の目的は、前記筋細胞分化促進剤を有効成分として含有する、老人性筋損失予防または治療用薬学組成物、または予防または改善用健康機能食品組成物を提供することにある。 That is, an object of the present invention is to provide a pharmaceutical composition for preventing or treating senile muscle loss or a health functional food composition for preventing or improving, which contains the above-described muscle cell differentiation promoter as an active ingredient.
前記目的を達するために、本発明はフェニルアラニン(Phe)及びメチオニン(Met)からなる筋細胞分化促進剤を提供する。 In order to achieve the above object, the present invention provides a myocyte differentiation promoter comprising phenylalanine (Phe) and methionine (Met).
本発明はまた、本発明による筋細胞分化促進剤を主成分として含有し、薬剤学的または食品学的に許容される添加剤を補助成分としてさらに含有する、筋細胞分化促進用組成物を提供する。 The present invention also provides a composition for promoting myocyte differentiation, which contains the myocyte differentiation promoting agent according to the present invention as a main component and further contains a pharmaceutically or food-acceptable additive as an auxiliary component. To do.
本発明はまた、本発明による筋細胞分化促進用組成物を含有する、老人性筋損失予防または治療用薬学組成物を提供する。 The present invention also provides a pharmaceutical composition for preventing or treating senile muscle loss, comprising the composition for promoting myocyte differentiation according to the present invention.
本発明はまた、本発明による筋細胞分化促進用組成物を含有する、老人性筋損失予防または改善用健康機能食品組成物を提供する。 The present invention also provides a health functional food composition for preventing or improving senile muscle loss, comprising the composition for promoting myocyte differentiation according to the present invention.
本発明の筋細胞分化促進用組成物及びこれを含有する薬学組成物または健康機能食品組成物は、筋芽細胞が筋肉細胞に分化されることを促進して筋肉減少症や筋損失を予防、改善及び治療することができ、特に老人性筋損失に効果的であり、筋細胞数の増加により基礎代謝量が増加して体内脂肪酸を酸化させるという効果を奏する。 The composition for promoting the differentiation of muscle cells of the present invention and the pharmaceutical composition or health functional food composition containing the same promote the differentiation of myoblasts into muscle cells to prevent sarcopenia and muscle loss. It can be improved and treated, and is particularly effective for senile muscle loss. The increase in the number of muscle cells increases the basal metabolic rate and oxidizes body fatty acids.
他の式で定義されない限り、本明細書で用いられた全ての技術的及び科学的用語は本発明が属する技術分野において熟練された専門家によって通常的に理解されるのと同じ意味を有する。一般的に、本明細書で用いられた命名法は本技術分野で周知の通常的に用いられるのである。 Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In general, the nomenclature used herein is commonly used in the art.
本発明で用いられる「筋芽細胞(myoblast)」とは筋肉細胞への分化能力を有する幹細胞を意味する。これら筋芽細胞は特異的に衛星細胞(satellite cells)に逆分化されることもあるが、長期間筋肉細胞への転換が発生しない一部筋芽細胞で起きる現象である。しかし、このような衛星細胞でも適切な刺激(運動など)が与えられると、いつでも筋芽細胞から筋肉細胞への分化が可能である。 As used herein, “myoblast” means a stem cell having the ability to differentiate into muscle cells. These myoblasts may be specifically reverse differentiated into satellite cells, but this phenomenon occurs in some myoblasts that do not undergo long-term conversion to muscle cells. However, such satellite cells can differentiate from myoblasts to muscle cells at any time when given an appropriate stimulus (such as exercise).
本発明で用いられる「筋芽細胞分化」とは単核の筋芽細胞が融合を通じて多核の筋管(myotube)を形成する過程である。筋芽細胞から筋管への分化過程で、ミオシンD(MyoD)、ミオゲニン(myogenin)などの遺伝子の発現が増加する。従って、筋芽細胞分化マーカー遺伝子としてミオシンDとミオゲニンを利用すれば筋細胞の分化有無を確認することができる。 “Myoblast differentiation” used in the present invention is a process in which mononuclear myoblasts form multinucleated myotubes through fusion. In the process of differentiation from myoblasts to myotubes, the expression of genes such as myosin D (MyoD) and myogenin increases. Therefore, if myosin D and myogenin are used as myoblast differentiation marker genes, the presence or absence of myocyte differentiation can be confirmed.
本発明で用いられる「筋肉細胞分化形成」とは、筋芽細胞が分化されて長い模様への変化と共に筋纎維及び多数のミトコンドリア含有など筋肉の特性を有する筋肉細胞が形成されることを意味し、形成された筋肉細胞が融合を経て多核の筋管(myotube)を形成することを意味する。ただし、細胞融合を通じた筋管形成は骨格筋のみで起きる現象であり、心筋及び平滑筋では起きない。 The term “muscle cell differentiation / formation” used in the present invention means that myoblasts are differentiated to form muscle cells having characteristics of muscle such as myofiber and containing many mitochondria together with a change to a long pattern. This means that the formed muscle cells form a multinucleated myotube through fusion. However, myotube formation through cell fusion is a phenomenon that occurs only in skeletal muscle and not in myocardium and smooth muscle.
本発明で用いられる幹細胞「分化」は幹細胞で特定細胞に完全に分化された場合だけでなく、幹細胞で特定細胞へ完全に分化される前の中間段階も含む。 The stem cell “differentiation” used in the present invention includes not only a case where a stem cell is completely differentiated into a specific cell, but also an intermediate stage before the stem cell is completely differentiated into a specific cell.
以下、本発明について具体的に説明する。 Hereinafter, the present invention will be specifically described.
本発明ではフェニルアラニン及びメチオニンを含む9種のアミノ酸(Leu、Ile、Met、Val、Lys、Trp、Phe、Thr、Gln)の中でどのアミノ酸が筋肉細胞の分化形成に影響を及ぼすのか確認するための実験を行った。その結果、特にフェニルアラニン(Phe)とメチオニン(Met)が欠乏された場合、筋肉細胞の分化形成が大きく阻害されることが分かり、フェニルアラニンとメチオニンの混合比率が重量比で2:1の場合、筋肉細胞の分化形成が最も大きく起きることを確認することができた。 In the present invention, in order to confirm which amino acid among 9 types of amino acids (Leu, Ile, Met, Val, Lys, Trp, Phe, Thr, Gln) including phenylalanine and methionine affects the differentiation formation of muscle cells. The experiment was conducted. As a result, especially when phenylalanine (Phe) and methionine (Met) are deficient, it is found that differentiation formation of muscle cells is greatly inhibited. When the mixing ratio of phenylalanine and methionine is 2: 1 by weight, It was confirmed that the most differentiated formation of cells occurred.
従って、本発明は一観点で、フェニルアラニン(Phe)及びメチオニン(Met)からなる筋細胞分化促進剤に関する。 Therefore, this invention relates to the myocyte differentiation promoter which consists of phenylalanine (Phe) and methionine (Met) from one viewpoint.
本発明において、前記筋細胞分化促進剤の前記フェニルアラニン(Phe)及びメチオニン(Met)は1:4〜4:1、好ましくは2:1の重量比で混合することを特徴とすることができる。前記重量比で含まれる場合、筋肉細胞の分化形成効果を現わすのに適切であるだけでなく、組成物の安定性及び安全性を全部満足することができ、費用対比効果の側面でも上記の範囲で含むことが適切である。 In the present invention, the myelin differentiation promoting agent phenylalanine (Phe) and methionine (Met) may be mixed in a weight ratio of 1: 4 to 4: 1, preferably 2: 1. When included in the weight ratio, it is not only suitable for exhibiting the differentiation formation effect of muscle cells, but also can satisfy all of the stability and safety of the composition. It is appropriate to include in the range.
また、前記フェニルアラニン及び/またはメチオニンは単量体、オリゴマー、重合体などで存在することができる。 The phenylalanine and / or methionine may be present as a monomer, oligomer, polymer, or the like.
本発明は他の観点で、本発明による筋細胞分化促進剤を主成分として含有し、薬剤学的または食品学的に許容される添加剤を補助成分としてさらに含有する、筋細胞分化促進用組成物に関する。 Another aspect of the present invention is a composition for promoting myocyte differentiation, which contains the myocyte differentiation promoter according to the present invention as a main component and further contains a pharmaceutically or food-acceptable additive as an auxiliary component. Related to things.
また、本発明において、前記筋細胞分化促進用組成物はトレオニン(Thr)、バリン(Val)、イソロイシン(Ile)、グルタミン(Gln)及びリシン(Lys)からなる群で選択された何れか1種以上のアミノ酸を補助成分としてさらに含有することを特徴とすることができる。 In the present invention, the composition for promoting myocyte differentiation is any one selected from the group consisting of threonine (Thr), valine (Val), isoleucine (Ile), glutamine (Gln), and lysine (Lys). It may be characterized by further containing the above amino acids as auxiliary components.
また、前記フェニルアラニン(Phe)は組成物総重量に対して0.02〜64重量%、好ましくは0.05〜54重量%で含有され、メチオニン(Met)も0.02〜64重量%、好ましくは0.05〜27重量%で含有されることを特徴とすることができる。前記二つのアミノ酸含量の総和が0.1重量%未満である場合効果が微弱であり、80重量%を超える場合、アミノ酸の代謝に問題のある患者は高フェニルアラニン血症(フェニルケトン尿症外)や高メチオニン血症(高ホモシステイン血症外)が発生する可能性がある。従って、正常人の場合は問題がないが、アミノ酸代謝異常患者を考慮した場合、フェニルアラニン/メチオニン混合製剤の量を組成物総重量に対して0.1〜80重量%の間で用いることが好ましい。 The phenylalanine (Phe) is contained in an amount of 0.02 to 64% by weight, preferably 0.05 to 54% by weight, based on the total weight of the composition, and methionine (Met) is preferably 0.02 to 64% by weight, preferably. May be contained at 0.05 to 27% by weight. If the sum of the two amino acid contents is less than 0.1% by weight, the effect is weak. If it exceeds 80% by weight, the patient having a problem with amino acid metabolism is hyperphenylalaninemia (excluding phenylketonuria). And hypermethionineemia (outside hyperhomocysteinemia) may occur. Therefore, although there is no problem in the case of normal persons, it is preferable to use the amount of the phenylalanine / methionine mixed preparation between 0.1 to 80% by weight with respect to the total weight of the composition in consideration of patients with abnormal amino acid metabolism. .
本発明は他の観点で、本発明による筋細胞分化促進剤を有効成分として含有する老人性筋損失予防または治療用薬学組成物に関する。 In another aspect, the present invention relates to a pharmaceutical composition for preventing or treating senile muscle loss, which contains the myocyte differentiation promoter according to the present invention as an active ingredient.
本発明による組成物を薬学組成物に適用する場合には、前記組成物を有効成分として常用される無機または有機担体を加えて、固体、半固体または液状の形態で製剤化することができる。本発明の有効成分を常法によって実施すれば容易に製剤化することができ、界面活性剤、賦形剤、着色剤、香辛料、安定化剤、防腐剤、保存剤、水和剤、乳化促進剤、懸濁剤、滲透圧を調節するための塩及び/または緩衝剤、その他常用の補助剤を適当に用いることができる。 When the composition according to the present invention is applied to a pharmaceutical composition, it can be formulated into a solid, semi-solid or liquid form by adding an inorganic or organic carrier commonly used as an active ingredient. If the active ingredient of the present invention is carried out by a conventional method, it can be easily formulated into a surfactant, excipient, coloring agent, spice, stabilizer, preservative, preservative, wettable powder, emulsification promotion. Agents, suspensions, salts and / or buffers for adjusting osmotic pressure, and other commonly used adjuvants can be appropriately used.
前記経口投与のための製剤としては錠剤、丸剤、顆粒剤、軟硬質カプセル剤、散剤、細粒剤、粉剤、液剤、懸濁剤、乳濁剤、シロップ剤、ペレット剤などを挙げることができる。これら剤形は有効成分以外に希釈剤(例:ラクトース、デキストロース、スクロース、マンニトール、ソルビトール、セルロース及びグリシン)、滑沢剤(例:シリカ、タルク、ステアリン酸及びそのマグネシウムまたはカルシウム塩及びポリエチレングリコール)を含有することができる。錠剤はまたマグネシウムアルミニウムシリケート、澱粉ペースト、ゼラチン、トラガカント、メチルセルロース、ナトリウムカルボキシメチルセルロースまたはポリビニルピロリドンのような結合剤を含有することができ、場合によっては、澱粉、寒天、アルギン酸またはそのナトリウム塩のような崩壊剤、吸収剤、着色剤、香味剤または甘味剤などの薬剤学的添加剤を含有することができる。前記錠剤は通常的な混合、顆粒化またはコーティング方法によって製造されることができる。 Examples of the preparation for oral administration include tablets, pills, granules, soft and hard capsules, powders, fine granules, powders, solutions, suspensions, emulsions, syrups, pellets, etc. Can do. In addition to the active ingredients, these dosage forms include diluents (eg, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and glycine), lubricants (eg, silica, talc, stearic acid and its magnesium or calcium salts and polyethylene glycol) Can be contained. Tablets can also contain binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose or polyvinylpyrrolidone, and in some cases, such as starch, agar, alginic acid or its sodium salt Pharmaceutical additives such as disintegrants, absorbents, colorants, flavoring agents or sweetening agents can be included. The tablets can be manufactured by conventional mixing, granulating or coating methods.
本発明による前記薬学組成物は経口、非経口、直腸、局所、経皮、静脈内、筋肉内、腹腔内、皮下などに投与されることができる。 The pharmaceutical composition according to the present invention can be administered orally, parenterally, rectally, topically, transdermally, intravenously, intramuscularly, intraperitoneally, subcutaneously and the like.
また、前記有効成分の投与量は治療を受ける対象の年齢、性別、体重または治療する特定疾患または病理状態、疾患または病理状態の深刻度、投与経路または処方者の判断によって変わることができる。このような因子に基づいた投与量の決定は当業者の水準内にある。一般的な投与量は、好ましくは1.375mg/kg/日〜1100mg/kg/日になることがあるが、前記投与量はいかなる方法でも本発明の範囲を限定するのではない。 The dosage of the active ingredient may vary depending on the age, sex, weight or specific disease or pathological condition to be treated, the severity of the disease or pathological condition, the route of administration or the judgment of the prescriber. Determination of dosage based on such factors is within the level of ordinary skill in the art. Typical dosages may preferably be between 1.375 mg / kg / day to 1100 mg / kg / day, but the dosages do not limit the scope of the invention in any way.
本発明はまた他の観点で、本発明による筋細胞分化促進剤を有効成分として含有する老人性筋損失予防または改善用健康機能食品組成物に関する。 In another aspect, the present invention also relates to a health functional food composition for preventing or ameliorating senile muscle loss, comprising the myocyte differentiation promoter according to the present invention as an active ingredient.
前記健康機能食品組成物の剤形は特に限定されないが、例えば、錠剤、顆粒剤、ドリンク剤、キャラメル、ダイエットバー、飲み物などに剤形化されることができる。各剤形の食品組成物は有効成分以外に当該分野で通常用いられる各種成分を剤形または使用目的によって当業者が困難なく簡単に適宜選定して配合することができ、他の原料と同時に適用する場合上昇効果を奏することができる。 The dosage form of the health functional food composition is not particularly limited, and can be formulated into tablets, granules, drinks, caramel, diet bars, drinks, and the like. In addition to the active ingredients, each dosage form of the food composition can be appropriately selected and formulated by the person skilled in the art without difficulty according to the dosage form or purpose of use, and can be combined with other ingredients. If you do, you can have a rising effect.
前記有効成分の投与量の決定は当業者の水準内にあり、この1日投与用量は投与しようとする対象の年齢、健康状態、合併症などの多様な要因によって変わることがある。 The determination of the dosage of the active ingredient is within the level of ordinary skill in the art, and this daily dosage may vary depending on various factors such as the age, health status, and complications of the subject to be administered.
以下、実施例を通じて本発明についてより詳しく説明する。これら実施例はただ本発明を例示するためのものであり、本発明の範囲がこれら実施例によって制限されることに解釈されないことは本技術分野において通常の知識を有する者にとって自明である。従って、本発明の実質的な範囲は添付される特許請求範囲及びそれらの等価物によって定義されると言える。 Hereinafter, the present invention will be described in more detail through examples. These examples are merely to illustrate the present invention, and it is obvious to those skilled in the art that the scope of the present invention is not construed to be limited by these examples. Accordingly, the substantial scope of the present invention may be defined by the appended claims and their equivalents.
[試験例1]必須アミノ酸欠乏による筋肉細胞分化形成効果確認
9種のアミノ酸(Leu、Ile、Met、Val、Lys、Trp、Phe、Thr、Gln)中の何れか一つの欠乏状況でそれぞれC2C12筋肉細胞の分化形成過程をオリンパス社のCK40光学顕微鏡(40x)を利用して観察した結果、図1に示すように、9種のアミノ酸の中でフェニルアラニン(Phe)の欠乏状況は筋肉細胞の分化形成を深刻に阻害していることが分かり、メチオニン(Met)の欠乏がフェニルアラニンの次に筋肉細胞の分化形成をたくさん阻害していることを確認することができた。よって、フェニルアラニン及びメチオニンの十分な提供が筋肉細胞の形成に重要であることを確認することができた。
[Test Example 1] Confirmation of muscle cell differentiation formation effect due to essential amino acid deficiency C2C12 muscles in any one of 9 amino acids (Leu, Ile, Met, Val, Lys, Trp, Phe, Thr, Gln) As a result of observing the cell differentiation formation process using Olympus CK40 optical microscope (40x), as shown in FIG. 1, among the nine amino acids, phenylalanine (Phe) deficiency is the differentiation formation of muscle cells. It was found that methionine (Met) deficiency inhibited muscle cell differentiation after phenylalanine. Therefore, it was confirmed that sufficient provision of phenylalanine and methionine is important for the formation of muscle cells.
他種の筋肉細胞であるL6の細胞でも上記と同じ方法で分化形成過程を観察した結果、図2に示すように、C2C12と同様にフェニルアラニン欠乏が筋肉細胞の分化形成に及ぶす影響が最も大きく、メチオニン欠乏も大きな影響を及ぼすことが分かった。 As a result of observing the differentiation formation process in L6 cells, which are other types of muscle cells, in the same manner as described above, as shown in FIG. 2, the effect of phenylalanine deficiency on the differentiation formation of muscle cells is the largest as in C2C12. Also, methionine deficiency was found to have a significant effect.
前記二つの実験結果により、9種のアミノ酸が筋肉細胞分化形成に及ぶす影響を次のような手順で整理することができた。 Based on the results of the two experiments, the effects of nine amino acids on the formation of muscle cell differentiation could be arranged according to the following procedure.
総必須アミノ酸>Phe>Met>Thr=Val=Ile=Gln=Lys>Leu=Trp Total essential amino acids> Phe> Met> Thr = Val = Ile = Gln = Lys> Leu = Trp
総アミノ酸が欠乏された状況で筋肉細胞の分化形成に最も大きい影響を及ぼし(分化が最も遅い)、その次はフェニルアラニンの欠乏、その次はメチオニンの欠乏が大きな影響を及ぼした。トリプトファンの欠乏状況は筋肉細胞の分化形成に及ぶす影響が最も少ないことを確認することができた。 The total amino acid deficiency had the greatest effect on muscle cell differentiation (slowest differentiation), followed by phenylalanine deficiency, followed by methionine deficiency. It was confirmed that tryptophan deficiency had the least effect on muscle cell differentiation.
筋肉細胞の分化形成時に細胞の模様変化を観測するとともに、分化マーカータンパク質(ミオシンDとミオゲニン)の発現パターンを調べるために分化された筋肉細胞からタンパク質を抽出した後、ミオシンDとミオゲニン特異抗体を当該技術分野で通常用いられるウエスタンブロッティング方法に利用して比較分析した。図3に示すように、前記光学顕微鏡による観察結果と同様にフェニルアラニンが欠乏された状況で分化マーカータンパク質の発現も著しく減少されることを確認することができ、フェニルアラニンよりは影響が些細であるが、メチオニン欠乏も分化マーカータンパク質の発現を減少させることを確認することができた。 In addition to observing cell pattern changes during differentiation of muscle cells, and extracting proteins from differentiated muscle cells to investigate the expression pattern of differentiation marker proteins (myosin D and myogenin), myosin D and myogenin-specific antibodies Comparative analysis was performed using Western blotting methods commonly used in the art. As shown in FIG. 3, it can be confirmed that the expression of the differentiation marker protein is remarkably reduced in the situation where phenylalanine is deficient, as in the observation result by the optical microscope. It was confirmed that methionine deficiency also decreased the expression of differentiation marker protein.
[試験例2]フェニルアラニンの筋肉細胞分化形成効果確認
試験例1によれば、必須アミノ酸の中でフェニルアラニンが筋肉細胞分化形成に及ぶす影響が最も大きく現われ、フェニルアラニンの添加により筋肉細胞分化形成が促進されることができるのかを調べるために後続の実験を用意した。また、アミノ酸代謝経路でフェニルアラニンはタイロシン(Tyr)に転換されるという点を考慮して、筋肉細胞の形成にタイロシン欠乏が影響を及ぼすのか調べるための実験を一緒に行った。フェニルアラニンが欠乏された細胞培養液にタイロシンまたはフェニルアラニンをそれぞれ濃度別(0.2mM、0.4mM、0.8mM)添加した後、C2C12細胞とL6細胞それぞれの分化形成能力を試験例1と同じ方法で光学顕微鏡を利用して測定した。
Test Example 2 Confirmation of Muscle Cell Differentiation Formation Effect of Phenylalanine According to Test Example 1, the most significant effect of phenylalanine on the formation of muscle cell differentiation appears among the essential amino acids, and the addition of phenylalanine promotes the formation of muscle cell differentiation. Subsequent experiments were set up to see what could be done. In addition, considering the fact that phenylalanine is converted to tylosin (Tyr) in the amino acid metabolic pathway, an experiment was conducted together to examine whether tylosin deficiency affects muscle cell formation. After adding tylosin or phenylalanine at different concentrations (0.2 mM, 0.4 mM, 0.8 mM) to the cell culture medium lacking phenylalanine, the differentiation forming ability of each of C2C12 cells and L6 cells was the same as in Test Example 1. And measured using an optical microscope.
その結果、図4(C2C12)及び図5(L6)に示すように、タイロシンではなくフェニルアラニンが筋肉細胞の形成に濃度依存的に影響を及ぼすということが分かった。 As a result, as shown in FIG. 4 (C2C12) and FIG. 5 (L6), it was found that phenylalanine, rather than tylosin, affects muscle cell formation in a concentration-dependent manner.
また、それぞれの場合、筋肉細胞マーカー遺伝子の発現を確認するために、当該技術分野において通常用いられるqRT−PCR方法のように、分化された筋細胞でRNAを抽出し、これに基づいて相補的DNA(cDNA)を合成した後、qRT−PCR(quantitative real-time polymerase chain reaction)にミオシンD及びミオゲニンのPCRプライマーを利用してマーカー遺伝子のmRNA発現変化を観察した。 In each case, in order to confirm the expression of the muscle cell marker gene, RNA is extracted from the differentiated muscle cells as in the qRT-PCR method usually used in the art, and complementary based on this. After synthesizing DNA (cDNA), the mRNA expression change of the marker gene was observed by using PCR primer of myosin D and myogenin in qRT-PCR (quantitative real-time polymerase chain reaction).
その結果、図6(C2C12)及び図7(L6)に示すように、分化マーカー遺伝子であるMyo DのmRNA発現程度も濃度依存的に現われることを確認することができた。 As a result, as shown in FIG. 6 (C2C12) and FIG. 7 (L6), it was confirmed that the mRNA expression level of the differentiation marker gene Myo D also appeared in a concentration-dependent manner.
さらに、フェニルアラニンとタイロシンの筋肉細胞形成に対する影響を確認するために、アミノ酸が全部欠乏された細胞培養液にフェニルアラニンまたはタイロシンをそれぞれ濃度別(0.2mM、0.4mM、0.8mM)添加した後、C2C12細胞及びL6筋肉細胞の分化形成能力を前記と同じ方法でそれぞれ測定した。 In addition, in order to confirm the effects of phenylalanine and tylosin on muscle cell formation, after adding phenylalanine or tylosin for each concentration (0.2 mM, 0.4 mM, 0.8 mM) to the cell culture medium completely depleted of amino acids. The ability of C2C12 cells and L6 muscle cells to form differentiation was measured by the same method as described above.
その結果、図8(C2C12)及び図9(L6)に示すように、タイロシンではないフェニルアラニンが添加された時、筋肉形成能力が増大されるという結果をもう一度確認することができた。また、図10(C2C12)及び図11(L6)に示すように、各筋肉細胞内マーカー遺伝子の発現もフェニルアラニンの添加のみによって増加することを確認することができた。 As a result, as shown in FIG. 8 (C2C12) and FIG. 9 (L6), when phenylalanine, which is not tylosin, was added, the result that muscle forming ability was increased could be confirmed once more. Moreover, as shown in FIG. 10 (C2C12) and FIG. 11 (L6), it was confirmed that the expression of each muscle cell marker gene was increased only by the addition of phenylalanine.
[試験例3]メチオニンの筋肉細胞分化形成効果確認
試験例1の結果を通じて、メチオニンはフェニルアラニンほどではないが、その外他の必須アミノ酸に比べて筋肉細胞分化形成に及ぶす影響が大きいことを類推することができた。これと関連して、メチオニンの添加によっても筋肉細胞の分化形成が可能であるか調べるために、アミノ酸が欠乏されたC2C12及びL6細胞にメチオニンを添加した後、筋肉細胞への分化の有無をそれぞれ観察した。
[Test Example 3] Confirmation of muscle cell differentiation formation effect of methionine Through the results of Test Example 1, methionine is not as much as phenylalanine, but it is analogized that it has a greater effect on muscle cell differentiation than other essential amino acids. We were able to. In this connection, in order to examine whether differentiation of muscle cells is possible by addition of methionine, after addition of methionine to C2C12 and L6 cells lacking amino acids, the presence or absence of differentiation into muscle cells was determined. Observed.
その結果、図12(C2C12)及び図13(L6)に示すように、メチオニン単独でも筋肉細胞分化形成に影響を与えることを確認することができ、図14(C2C12)及び図15(L6)に示すように、筋肉細胞マーカー遺伝子の発現が増加することを通じてもメチオニンの筋肉細胞分化形成に影響を及ぼすことをもう一度確認することができた。 As a result, as shown in FIG. 12 (C2C12) and FIG. 13 (L6), it can be confirmed that methionine alone affects muscle cell differentiation, and FIG. 14 (C2C12) and FIG. 15 (L6) As shown, it was once again confirmed that methionine affects the formation of muscle cells by increasing the expression of muscle cell marker genes.
[実施例]フェニルアラニン及びメチオニンの混合比率による筋肉細胞形成効果確認
前記試験例1〜3でアミノ酸の中でフェニルアラニン及びメチオニンが筋肉細胞分化形成に最も効果が良かった点に着眼して、最適な効果を現わすフェニルアラニン及びメチオニンの混合比率を調べるために実施例1〜7を以下の表1の成分及び含量で製造した。比較例1はメチオニンを全く含まないように製造し、比較例2はフェニルアラニンを全く含まないようにして製造した。また筋肉細胞分化には些細な影響を及ぼすが、筋肉内タンパク質の合成を誘導すると知られた分岐鎖アミノ酸(ロイシン、バリン、イソロイシン)も少量添加した。
[Example] Confirmation of muscle cell formation effect by mixing ratio of phenylalanine and methionine Focusing on the point that phenylalanine and methionine were most effective for the differentiation of muscle cells among the amino acids in Test Examples 1 to 3, the optimal effect Examples 1 to 7 were prepared with the components and contents shown in Table 1 below to determine the mixing ratio of phenylalanine and methionine. Comparative Example 1 was prepared without any methionine, and Comparative Example 2 was prepared with no phenylalanine. In addition, a small amount of branched chain amino acids (leucine, valine, isoleucine), which are known to induce muscle protein synthesis, have a slight effect on muscle cell differentiation.
前記実施例1〜7と比較例1及び2を、試験例1〜3に記載されたのと同じ方法でC2C12細胞及びL6細胞に処理し、筋肉細胞の分化形成を観測及び測定した。その結果、図16(C2C12)及び図17(L6)に示すように、フェニルアラニンとメチオニンを2:1の重量比で混合した実施例3の筋肉細胞分化形成効果が最も優れることを確認することができた。 Examples 1 to 7 and Comparative Examples 1 and 2 were processed into C2C12 cells and L6 cells in the same manner as described in Test Examples 1 to 3, and the differentiation formation of muscle cells was observed and measured. As a result, as shown in FIG. 16 (C2C12) and FIG. 17 (L6), it is confirmed that the muscle cell differentiation forming effect of Example 3 in which phenylalanine and methionine are mixed at a weight ratio of 2: 1 is most excellent. did it.
以上、本発明内容の特定部分を詳しく記述したが、本技術分野における通常の知識を有する者にとってこのような具体的な技術はただ好ましい実施態様であるだけであり、それにより本発明の範囲が制限されるのではない点は明白であろう。従って、本発明の実質的な範囲は添付される特許請求範囲とそれらの等価物によって定義される。 Although specific portions of the contents of the present invention have been described in detail above, such specific techniques are merely preferred embodiments for those having ordinary knowledge in the technical field, and the scope of the present invention is thereby limited. It will be clear that it is not limited. Accordingly, the substantial scope of the present invention is defined by the appended claims and their equivalents.
また、以下本発明の組成物を含む薬学組成物及び健康機能食品組成物の剤形例をより詳しく説明するが、それによって本発明の範囲が制限されるのではないことは明白である。 Moreover, although the pharmaceutical composition containing the composition of this invention and the dosage-form example of a health functional food composition are demonstrated in more detail below, it is clear that the scope of the present invention is not restrict | limited by this.
[剤形例1]錠剤の製造
実施例3.............50mg
とうもろこし澱粉..........100mg
乳糖................100mg
ステアリン酸マグネシウム........2mg
ビタミンC...............50mg
[Dosage Form Example 1] Tablet Production Example 3 . . . . . . . . . . . . 50mg
Corn starch. . . . . . . . . . 100mg
lactose. . . . . . . . . . . . . . . . 100mg
Magnesium stearate. . . . . . . . 2mg
Vitamin C. . . . . . . . . . . . . . . 50mg
前記成分を混合した後、通常の錠剤製造方法によって打錠して錠剤を製造する。 After mixing the above ingredients, tablets are produced by tableting by a conventional tablet production method.
[剤形例2]カプセル剤の製造
実施例3...............50mg
とうもろこし澱粉..........100mg
乳糖................100mg
ステアリン酸マグネシウム.......2mg
ビタミンC..............50mg
セリン................50mg
[Dosage Form Example 2] Capsule Production Example 3 . . . . . . . . . . . . . . 50mg
Corn starch. . . . . . . . . . 100mg
lactose. . . . . . . . . . . . . . . . 100mg
Magnesium stearate. . . . . . . 2mg
Vitamin C. . . . . . . . . . . . . . 50mg
Serine. . . . . . . . . . . . . . . . 50mg
通常のカプセル剤の製造方法によって前記成分を混合してゼラチンカプセルに充填してカプセル剤を製造する。 The above ingredients are mixed and filled into gelatin capsules by a conventional capsule production method to produce capsules.
[剤形例3]液剤の製造
実施例3..............100mg
異性化糖................10g
マンニト−ル................5g
ビタミンC...............50mg
セリン.................50mg
油脂....................適量
精製水...................残量
[Dosage Form Example 3] Production Example 3 of Liquid Solution . . . . . . . . . . . . . 100mg
Isomerized sugar. . . . . . . . . . . . . . . . 10g
Mannitol. . . . . . . . . . . . . . . . 5g
Vitamin C. . . . . . . . . . . . . . . 50mg
Serine. . . . . . . . . . . . . . . . . 50mg
Oils and fats. . . . . . . . . . . . . . . . . . . . Appropriate amount of purified water. . . . . . . . . . . . . . . . . . . Remaining amount
通常の液剤製造方法によって精製水にそれぞれの成分を加えて溶解させ、レモン香を適量加えた後、前記成分を混合し、その後精製水を加えて全体100mlに調節した後、遮光ビンに充填し且つ滅菌して液剤を製造する。 Add each ingredient to purified water and dissolve it with the usual solution manufacturing method, add lemon fragrance in an appropriate amount, mix the ingredients, then add purified water to adjust the total volume to 100 ml, then fill into a light-shielding bottle. And sterilize to produce a solution.
[剤形例4]健康機能食品の製造
実施例3..............1000mg
ビタミン混合物
ビタミンA アセテート.........70μg
ビタミンE..............1.0mg
ビタミンB1.............0.13mg
ビタミンB2............0.15mg
ビタミンB6..............0.5mg
ビタミンB12.............0.2μg
ビタミンC...............10mg
ビオチン.................10μg
ニコチン酸アミド............1.7mg
葉酸....................50μg
パントテン酸カルシウム..........0.5mg
無機質混合物
硫酸第一鉄...............1.75mg
酸化亜鉛................0.82mg
炭酸マグネシウム............25.3mg
第1リン酸カルシウム............15mg
第2リン酸カルシウム............55mg
クエン酸カリウム..............90mg
炭酸カルシウム..............100mg
塩化マグネシウム.............24.8mg
[Formulation Example 4] Production Example of Health Functional Food Example 3. . . . . . . . . . . . . . 1000mg
Vitamin mixture vitamin A acetate. . . . . . . . . 70 μg
Vitamin E. . . . . . . . . . . . . . 1.0mg
Vitamin B1. . . . . . . . . . . . . 0.13mg
Vitamin B2. . . . . . . . . . . . 0.15mg
Vitamin B6. . . . . . . . . . . . . . 0.5mg
Vitamin B12. . . . . . . . . . . . . 0.2 μg
Vitamin C. . . . . . . . . . . . . . . 10mg
Biotin. . . . . . . . . . . . . . . . . 10 μg
Nicotinamide. . . . . . . . . . . . 1.7mg
Folic acid. . . . . . . . . . . . . . . . . . . . 50 μg
Calcium pantothenate. . . . . . . . . . 0.5mg
Inorganic mixture ferrous sulfate. . . . . . . . . . . . . . . 1.75mg
Zinc oxide. . . . . . . . . . . . . . . . 0.82mg
Magnesium carbonate. . . . . . . . . . . . 25.3mg
Primary calcium phosphate. . . . . . . . . . . . 15mg
Dicalcium phosphate. . . . . . . . . . . . 55mg
Potassium citrate. . . . . . . . . . . . . . 90mg
Calcium carbonate. . . . . . . . . . . . . . 100mg
Magnesium chloride. . . . . . . . . . . . . 24.8mg
前記ビタミン及びミネラル混合物の組成比は比較的健康食品に相応しい成分を好ましい実施例で混合したが、その配合比を任意に変形実施しても構わなく、通常の健康食品の製造方法によって前記成分を混合した後、顆粒を製造し、通常の方法によって健康機能食品組成物の製造に用いることができる。 The composition ratio of the vitamin and mineral mixture was mixed with components suitable for health foods in a preferred embodiment, but the blending ratio may be arbitrarily changed, and the ingredients may be changed by a normal health food manufacturing method. After mixing, a granule is manufactured and can be used for manufacturing a health functional food composition by an ordinary method.
[剤形例5]飲み物の製造
実施例3..............1000mg
クエン酸..............1000mg
オリゴ糖................100g
梅濃縮液..................2g
タウリン..................1g
精製水を加えて全体...........1000ml
[Form 5] Drink production example 3. . . . . . . . . . . . . . 1000mg
citric acid. . . . . . . . . . . . . . 1000mg
oligosaccharide. . . . . . . . . . . . . . . . 100g
Plum concentrate. . . . . . . . . . . . . . . . . . 2g
Taurine. . . . . . . . . . . . . . . . . . 1g
Add purified water to the whole. . . . . . . . . . . 1000ml
通常の飲み物の製造方法によって前記成分を混合した後、約1時間85℃で撹拌加熱する。作られた溶液を濾過して滅菌された2Lの容器に取得し、その後密封滅菌した後、冷蔵保管して本発明の飲み物組成物の製造に用いる。
The above ingredients are mixed by a usual method for producing a drink, and then stirred and heated at 85 ° C. for about 1 hour. The prepared solution is filtered to obtain a sterilized 2 L container, and then sterilized in a sealed manner, and then refrigerated for use in producing the drink composition of the present invention.
Claims (8)
Use of phenylalanine and methionine as myocyte differentiation promoters in the production of health functional food compositions.
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US20220331290A1 (en) * | 2019-09-24 | 2022-10-20 | Myo-Tec-Sci | Pharmaceutical composition for preventing or treating sarcopenia, containing unnatural amino acid |
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BRITISH JOURNAL OF NUTRITION, vol. 111, JPN6020014938, 2014, pages 201 - 206, ISSN: 0004501051 * |
J. AM. GERIATR. SOC., vol. 60, JPN6020014935, 2012, pages 16 - 23, ISSN: 0004259265 * |
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