CN114042083B - Muscle-building and therapeutic applications of tetrathiomolybdate - Google Patents
Muscle-building and therapeutic applications of tetrathiomolybdate Download PDFInfo
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- CN114042083B CN114042083B CN202111471789.5A CN202111471789A CN114042083B CN 114042083 B CN114042083 B CN 114042083B CN 202111471789 A CN202111471789 A CN 202111471789A CN 114042083 B CN114042083 B CN 114042083B
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- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Abstract
The invention discloses application of tetrathiomolybdate in preparing products or medicines for realizing muscle enhancement, muscle function improvement, exercise capacity enhancement and prevention or treatment of diseases related to muscular systems, wherein the molecular general formula of the tetrathiomolybdate is X + MoS 4 2‑ Y + Wherein the positions of the ionic bonds of the 4 sulfide ions are interchangeable; x + And Y + Are the same or different cations. The invention provides application of tetrathiomolybdate in preparing products or medicines capable of realizing muscle growth, muscle function improvement, exercise capacity enhancement and muscle system related disease prevention or treatment, which can not only increase muscle mass, muscle protein content and muscle fiber cross-sectional area, but also promote differentiation of myoblasts and activate mTOR muscle growth signal pathway, and does not cause liver function damage and increase body fat in the animal experiment process, and has remarkable effect.
Description
Technical Field
The invention belongs to application of thiomolybdate, and particularly relates to application of thiomolybdate in the fields of muscle enhancement, muscle function improvement, exercise capacity enhancement, prevention or treatment of diseases related to a muscle system and the like.
Background
Muscle is the most abundant protein reservoir in the human body and has important regulatory effects on body health and glycolipid metabolism (Sartori et al, Nat Commun 2021, 12, 330). However, under normal conditions, the skeletal muscle of human body is continuously attenuated with the increase of age, generally, after the age of 50, the skeletal muscle is averagely reduced by 1-2% every year, and the normal function of the skeletal muscle is influenced by 30% of muscle reduction, so that sarcopenia (sarcopenia) occurs. Under a variety of pathological conditions (e.g., endocrine function changes, chronic diseases, inflammation, insulin resistance, and nutritional deficiencies), muscle mass is more likely to decline rapidly, resulting in abnormal muscle function (Fielding et al, J Am Med Dir Assoc 2011, 12, 249-. Among other things, a decrease in muscle mass also affects muscle function, leading to decreased motor function, imbalance in energy homeostasis, and increased risk of chronic disease (Sartori et al, Nat Commun 2021, 12, 330). Therefore, maintaining a moderate muscle mass throughout the life cycle is not only beneficial for enhancing motor function, but also beneficial for improving the health of the body.
Muscle hypertrophy is a scientific term for muscle augmentation, the theoretical basis of which is that muscle protein synthesis is increased and breakdown is reduced. On a molecular level, the main signaling pathways for regulating muscle protein growth include IGF1-PI3K-Akt-mTOR, myostatin-Smad 3, and the like; at the cellular level, myogenic differentiation factor (MyoD) initiates the expression of a series of myogenic specific genes and induces differentiation of myosatellite cells into myoblasts. Myogenin (MyoG), expressed by myoblasts, promotes fusion of myocytes with each other to form myotubes, and ultimately, muscles. The ideal myogenic mode of action therefore involves both stimulation of muscle protein synthesis and promotion of differentiation of muscle satellite cells and myotube formation.
At present, the means of muscle development mainly include resistance exercise, nutritional supplementation and medication. The application population of the anti-resistance exercise has certain limitations, such as inapplicability to the elderly with weak mobility and patients with acute diseases; nutritional supplementation (primarily protein) simply addresses the problem of increasing nutritional requirements in muscle and is prone to obesity. Therefore, in recent years, muscle-building drugs have been receiving attention. China is already in the aging stage and the degree is further deepening, which undoubtedly leads to the occurrence rate of muscle loss and muscle dysfunction being greatly increased. Therefore, the development of a novel muscle-increasing drug with high efficiency and safety so as to achieve the purposes of optimizing muscle mass and preventing and treating diseases of the muscle system is more critical and urgent in clinical needs.
The existing muscle-increasing drugs mainly focus on the aspects of improving appetite, regulating inflammation, intervening synthesis and catabolism, and the like, such as ghrelin, testosterone, hydroxymethylbutyrate, and the like, but most commercially available muscle-increasing drugs have certain side effects and great risks to health, so the use of the existing muscle-increasing drugs is still controversial. Even if the safety of some muscle-increasing medicines meets the medical approval requirements, the part of the commercially available products or medicines with the muscle-increasing function are mainly developed for athletes or sports people, and the muscle-increasing appeal of other people (such as the elderly, patients with muscle loss and muscle dysfunction) cannot be met.
Accordingly, the development of a general type and high safety muscle-increasing product or drug which can improve exercise capacity by increasing muscle and prevent and treat muscular system diseases has become a technical problem to be solved in the art.
In addition, in the application of tetrathiomolybdate, the prior art shows: tetrathiomolybdate can act as a sulfide donor or copper ion chelator (Dyson et al, PLoS Med 2017, 14, e 1002310), but the specific action target molecule is not fully understood. Therefore, the application of thiomolybdate is limited at present. According to the data of drug Bank (https:// go. drug bank. com/drugs), the current clinical application and clinical trial mainly utilize the function of tetrathiomolybdate as a copper ion chelating agent, and the only approved clinical application is the treatment of Wilson's disease (abnormal accumulation of copper ions), and 17 other clinical trials are in progress, mainly relating to tumor treatment.
In the studies of tetrathiomolybdate in relation to muscle, the prior art only involves two aspects: one related to the treatment of myocardial infarction (EP 2578221A 1; US10781162B 2) and the other related to the treatment of amyotrophic lateral sclerosis (Tokuda et al, Neurobiol Dis 2013, 54, 308-319). In applications related to the treatment of myocardial infarction, tetrathiomolybdate can reduce the oxygen consumption rate of organisms or organs, so that the tetrathiomolybdate can be potentially applied to diseases related to myocardial infarction (Dyson et al, PLoS Med 2017, 14, e 1002310), but the technology only relates to the improvement of myocardial infarction caused by ischemia-reperfusion and does not relate to the function of muscles. In applications involving the treatment of amyotrophic lateral sclerosis, it is primarily considered that amyotrophic lateral sclerosis is a serious neuromuscular disease characterized by degenerative loss of motor neurons, often leading to severe muscle loss, even paralysis and death within 2-5 years after onset (Gil-Bea et al, Expert Rev Mol Med 2017, 19, e 7). Since abnormalities in copper homeostasis are considered to be one of the causes of motor neuron damage (Gil-Bea et al, Expert Rev Mol Med 2017, 19, e 7), there are studies considering: tetrathiomolybdate slows the degenerative loss of motor neurons by chelating copper ions, thereby slowing muscle loss (Tokuda et al, Neurobiol Dis 2013, 54, 308-one 319). Clearly, this technique involves only muscle wasting and does not involve muscle augmentation. Furthermore, paradoxically, oxidative stress is considered to be the core causative factor of amyotrophic lateral sclerosis (Miana-Mena et al, J Neurol 2011, 258, 762-. Also because of this, the data for the treatment of amyotrophic lateral sclerosis by tetrathiomolybdate by chelating copper ions remains largely controversial. In summary, although tetrathiomolybdate has been implicated in muscle-related studies, no such technique has been described to date as being able to promote muscle enhancement by tetrathiomolybdate, nor has there been any theory to which the prior art has been led or inferred that tetrathiomolybdate promotes muscle enhancement.
Disclosure of Invention
The technical problem to be solved by the invention is to overcome the defects and defects mentioned in the background technology, and provide a simple, convenient, low-cost, good-effect and good-safety tetrathiomolybdate for preparing products or medicines capable of enhancing muscle, improving muscle function, enhancing motor ability and preventing or treating diseases related to the muscle system.
In order to solve the technical problems, the technical scheme provided by the invention is the application of tetrathiomolybdate in preparing products or medicines capable of increasing muscle, improving muscle function, enhancing motor ability and preventing or treating diseases related to a muscle system.
In the above application, it is preferable that the tetrathiomolybdate (English name: tetrathiomolybdate) has a molecular formula of X + MoS 4 2- Y + The structural formula is as follows:
wherein the positions of the ionic bonds of the 4 sulfide ions are interchangeable; x + And Y + Are the same or different cations.
In the above application, preferably, the cation is one capable of dissociating in solution to generate MoS 4 2- Or can be enzymatically hydrolyzed in a biological system to produce MoS 4 2- Inorganic cations and/or organic cations. Because our experiments show that the active units of the tetrathiomolybdate are mainly tetrathiomolybdate ions (MoS) 4 2- ) Therefore, the range of the selectable cations is wider, and the selectable and adjustable space of the later product is larger.
In the above application, preferably, the inorganic cation comprises Na + 、K + 、NH 4 + At least one of; the organic cation comprises at least one of amine ions and choline ions.
In the above application, preferably, the inorganic cation comprises NH 4 + (ii) a The organic cation comprises a choline ion.
In the above application, the muscle growth preferably includes at least one of promoting proliferation of myoblasts, promoting differentiation of myoblasts into myocytes, and increasing muscle mass in the body.
In the above application, preferably, the improvement of the muscle function includes at least one of enhancement of a muscle stretching function, enhancement of a muscle motor function, improvement of a muscle endocrine function, improvement of a muscle metabolic function, and enhancement of a muscle ability to regulate blood sugar. Existing theoretical studies indicate that muscles, in addition to motor and metabolic organs, are endocrine organs which have important regulatory effects on the metabolism of the body by secreting various endocrine factors, while muscle mass is the determining factor for their function (see Giudice et al, Curr Opin Pharmacol 2017, 34, 49-55, Iizuka et al, J Pharmacol Sci 2014, 125-. Therefore, the maintenance of stable muscle quality is the guarantee of the functions of maintaining the strength output, endocrine, regulating and controlling metabolism and the like of the muscle, so that the increase of the muscle has important significance for improving the endocrine function, the metabolic function and the blood sugar regulation capability of the muscle.
In the above-mentioned application, preferably, the disease associated with the muscular system includes at least one of myasthenia, sarcopenia, dermatomyositis, progressive muscular dystrophy, congenital myopathy, metabolic myopathy, infectious myopathy, concomitant myopathy, mitochondrial myopathy, rhabdomyolysis, and cachexia.
In the above application, preferably, the exercise capacity is enhanced for a specific group of athletes, elderly people, and patients with muscle loss or muscle dysfunction.
Numerous studies have shown that the decrease in muscle mass not only directly results in the decrease in motor ability and imbalance in energy metabolism homeostasis, and accelerates the development of diseases in the muscle system, but also indirectly increases the risk of various chronic diseases, and leads to an increase in the mortality of the population (Isoyama et al, Clin J Am Soc Nephrol 2014, 9, 1720-. Therefore, maintaining a moderate muscle mass throughout the life cycle is not only beneficial to enhance motor function, improve endocrine and metabolic functions, reduce the occurrence of diseases of the muscular system, but also beneficial to improve the health of the body, reduce the risk of the occurrence of various chronic diseases, and reduce the all-cause mortality.
In the above application, preferably, the tetrathiomolybdate is prepared into 1 nmol/L-200 mmol/L or 1 nmol/Kg-200 mmol/Kg nutrient solution or pharmaceutical solution which can be orally taken, drunk or injected, or prepared into solid nutrient composition or pharmaceutical composition.
In the above applications, it is preferable that the nutrient solution, pharmaceutical solution, nutritional composition or pharmaceutical composition comprises at least one of a pharmaceutically acceptable diluent, excipient, adjuvant or existing muscle-building agent.
In the above application, preferably, the tetrathiomolybdate is prepared into a health product, a functional food or a functional drink, and the tetrathiomolybdate is used as a main functional component or an auxiliary functional component.
In the above application, preferably, the tetrathiomolybdate is used for preparing products or medicines which do not cause obesity and/or have no liver injury toxicity and/or no nervous system injury toxicity.
Compared with the prior art, the invention has the following beneficial effects: the invention provides the application of tetrathiomolybdate in preparing products or medicines capable of realizing muscle growth, improving muscle functions, enhancing motor ability and preventing or treating diseases related to a muscle system, the application of tetrathiomolybdate can not only increase muscle mass, increase muscle protein content and muscle fiber cross-sectional area, but also promote differentiation of myoblasts and activate mTOR muscle growth signal pathways, and in the animal experiment process, liver function damage and body fat increase are not caused, and the effect is obvious.
The method of use and dosage of tetrathiomolybdate in the present invention depend on various factors including the administration route and the administration period, and the age, body weight, health condition, sex and dietary condition of the user. Thus, one of ordinary skill in the art will be able to determine the appropriate effective dose, dosage form, route of administration, or method of administration for each of the above-described uses.
Drawings
In order to more clearly illustrate the embodiments or technical solutions of the present invention, the drawings used in the embodiments or technical solutions in the prior art are briefly introduced below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and it is obvious for those skilled in the art that other drawings can be obtained according to these drawings without creative efforts.
FIG. 1 is a graph showing the effect of tetrathiomolybdate on Bioelectrical impedance index (Bioelectrical impedance index) of experimental animals in example 1 of the present invention.
FIG. 2 is a graph showing the effect of administration of tetrathiomolybdate on the weight index effect of gastrocnemius muscle (gastrocnemius) and rectus femoris muscle (rectus femoris) in experimental animals in example 1 of the present invention. (weight index is a value obtained by standardizing the weight of gastrocnemius or rectus femoris on the body weight of a mouse, which is calculated by dividing the weight of the intact gastrocnemius or rectus femoris by the weight of the mouse and multiplying by 100 in units of g/100g of body weight)
FIG. 3 is a graph showing the comparative effect of tetrathiomolybdate on the increase in total protein capacity of gastrocnemius muscle in experimental animals in example 1 of the present invention.
FIG. 4 is a graph showing the effect of tetrathiomolybdate on the change in the cross-sectional area of the fibers of the gastrocnemius muscle in the experimental animal in comparison with the cross-sectional area of the fibers of the gastrocnemius muscle in example 1 of the present invention.
FIG. 5 is a graph showing the effect of tetrathiomolybdate on the proportion of thicker muscle fibers in gastrocnemius muscle of experimental animals in comparison with the effect of tetrathiomolybdate in example 1 of the present invention.
FIG. 6 is a graph showing the effect of tetrathiomolybdate on mRNA expression of a molecule involved in the musculus gastrocnemius mTOR myogenic signaling pathway in experimental animals in comparison with example 1 of the present invention.
FIG. 7 is a graph showing the effect of tetrathiomolybdate on the weight index of subcutaneous fat and visceral fat in experimental animals in example 1 of the present invention.
FIG. 8 is a graph showing the effect of tetrathiomolybdate on the damage of hepatocytes of experimental animals in comparison with the effect of tetrathiomolybdate on the damage of hepatocytes of example 1 of the present invention [ test serum alanine Aminotransferase (ALT) ].
FIG. 9 is a graph showing the effect of tetrathiomolybdate on the damage of hepatocytes of experimental animals in comparison with the effect of tetrathiomolybdate on the damage of hepatocytes of example 1 of the present invention [ test for serum aspartate Aminotransferase (AST) ].
FIG. 10 is a graph showing the effect of tetrathiomolybdate on the differentiation rate of C2C12 cells in example 2 of the present invention.
FIG. 11 is a graph comparing the effects of tetrathiomolybdate on the expression of myogenin (MyoG) mRNA inducing differentiation of C2C12 cells in example 2 of the present invention.
FIG. 12 is a graph comparing the effect of tetrathiomolybdate on the expression of myosin (MyHc) mRNA formed by myotubes of C2C12 cells in example 2 of the present invention.
FIG. 13 is a graph showing the effect of tetrathiomolybdate on the swimming speed of test animals in the Morris water maze test in example 3 of the present invention.
FIG. 14 is a graph showing the effect of tetrathiomolybdate on the incubation period of experimental animals before the platform was found in the Morris water maze experiment in example 3 of the present invention.
FIG. 15 is a graph showing the effect of tetrathiomolybdate on the number of times the test animal crosses the hidden platform in the Morris water maze test in example 3 of the present invention.
FIG. 16 is a graph comparing the effect of different tetrathiomolybdates on the proliferation of C2C12 cells in example 4 of the present invention.
In each of the above figures, TM is tetrathiomolybdate treatment group. Data results are expressed as mean ± sem, with lower case english letters representing TM statistically significant relative to the control, where: a represents p < 0.05, b represents p < 0.01, c represents p < 0.005, and d represents p < 0.001.
Detailed Description
In order to facilitate understanding of the invention, the invention will be described more fully and in detail with reference to the accompanying drawings and preferred embodiments, but the scope of the invention is not limited to the specific embodiments below.
Unless otherwise defined, all terms of art used hereinafter have the same meaning as commonly understood by one of ordinary skill in the art. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention.
Unless otherwise specifically stated, various raw materials, reagents, instruments, equipment and the like used in the present invention are commercially available or can be prepared by existing methods.
Example 1:
this example provides an example of a demonstration of muscle building function of tetrathiomolybdate at the animal level.
Using a healthy mouse model, the muscle-building effect of administration of tetrathiomolybdate (ammonium tetrathiomolybdate was specifically used in this example) was observed in the mouse model, and the changes in the respective indices at the molecular biological level of the animals to be tested were analyzed.
The experimental procedure was as follows:
1) experimental animals: male C57BL/6J mice, SPF grade, weighing 24 + -1 g, purchased from Schlekschada laboratory animals, Inc. in Hunan, were randomly divided into tetrathiomolybdate-treated and control groups of 6 mice each. Feeding animals in SPF cage at 22 deg.C and proper humidity;
2) feeding operation: the animal adaptation stage comprises recording the weight of the animal at 14:00 per day, recording the change of food weight per 24 hours to calculate the food intake per unit weight, and observing the mental state and the excrement form of the animal;
3) the tetrathiomolybdate treatment method comprises the following steps: the tetrathiomolybdate is respectively added into drinking water, diet, pills and the like according to a certain proportion for treatment, or is prepared into solution and then is treated by gastric lavage or different injection methods, and a certain muscle-increasing effect can be exerted under the condition that the treatment dosage is 38.4nmol/kg body weight to 768 μmol/kg body weight, and the following concrete steps of various treatment methods are carried out:
3.1) specific implementation steps of adding tetrathiomolybdate to the ration:
i) taking a healthy animal model (such as: mouse, rat), weighing the weight and grain intake daily for one week, and calculating the ratio of the grain intake to the weight;
ii) treatment dosage based on tetrathiomolybdate to be explored (e.g.: x mu mol/kg body weight), dividing the treatment dosage by the ratio of the grain intake amount per day to the body weight, and preparing grains containing corresponding dosage of tetrathiomolybdate in advance;
iii) during the treatment period, animals of the treatment group were allowed to eat a diet containing tetrathiomolybdate and the control group was allowed to eat a diet without added tetrathiomolybdate;
iv) after the grains are well prepared and formed, the grains are prepared as soon as possible, and when the grains need to be stored, the grains need to be sealed at low temperature and protected from light.
3.2) adding tetrathiomolybdate into the drinking water:
i) taking a healthy animal model (such as: mouse, rat), measuring the weight and water intake of the mouse and rat every day for one week continuously, and calculating the ratio of the water intake to the weight every day;
ii) treatment dosage based on tetrathiomolybdate to be explored (e.g.: x μmol/kg body weight), dividing the treatment dose by the 'ratio of daily water intake to body weight', and preparing drinking water containing corresponding dose of tetrathiomolybdate;
iii) during the treatment period, animals of the treated group were allowed to drink water containing tetrathiomolybdate and the control group was given water containing no tetrathiomolybdate;
iv) drinking water needs to be changed once a day and is ready for use.
3.3) specific implementation steps of tetrathiomolybdate pill administration:
i) taking a healthy animal model (such as: mouse, rat) and weighing the body weight of the mice and rats every day;
ii) dosage based on tetrathiomolybdate to be explored (e.g.: x mu mol/kg body weight) to determine the mixing ratio of tetrathiomolybdate and excipient (wherein, a certain amount of bacon can be properly added into the excipient, which is convenient for training animals to independently take pills);
iii) fully and uniformly mixing tetrathiomolybdate with an excipient, tabletting, and freezing and storing;
iv) the first three days of administration are a training period for the animals to actively take pills, i.e. within the three days, the animals are starved for 6-8 hours each day before administration, the animals are trained to actively take pills, the animals in the experimental group are made to take pills containing tetrathiomolybdate, and the animals in the control group are made to take full excipient pills not containing tetrathiomolybdate;
v) pill is regularly administered every day, and a batch of pills is newly prepared for each batch of experiment.
3.4) the specific steps of the tetrathiomolybdate intragastric administration treatment:
i) taking a healthy animal model (such as: mouse, rat), the body weight of which was weighed daily;
ii) treatment dosage based on tetrathiomolybdate to be explored (e.g.: x [ mu ] mol/kg body weight) to prepare a tetrathiomolybdate solution with a certain concentration, and in order to facilitate perfusion quantification, the concentration of the tetrathiomolybdate solution is generally suitable for perfusing 1-10 [ mu ] L of the solution per gram of body weight;
iii) connecting a syringe with proper scales with a special stomach filling needle for animals, regularly filling the stomach of the animals every day, filling a solution containing tetrathiomolybdate into a treatment group, and filling a control solution not containing tetrathiomolybdate into a control group;
iv) the solution is ready for use each time.
3.5) the specific steps of the subcutaneous injection administration of tetrathiomolybdate are as follows:
i) taking a healthy animal model (such as: mouse, rat), the body weight of which was weighed daily;
ii) based on the dosage of tetrathiomolybdate to be explored (e.g.: x [ mu ] mol/kg body weight) to prepare a tetrathiomolybdate solution with a certain concentration, and in order to facilitate perfusion quantification, the concentration of the tetrathiomolybdate solution is generally suitable for perfusing 1-10 [ mu ] L of the solution per gram of body weight;
iii) selecting a proper syringe needle according to the size of the animal, selecting a syringe with proper scales according to the injection quantity required, and carrying out subcutaneous injection on the animal at regular time every day, wherein the experimental group is injected with a solution containing tetrathiomolybdate, and the control group is injected with a control solution not containing tetrathiomolybdate;
iv) during injection, the back of the animal is prohibited upwards, the skin of the back of the animal is slightly lifted by an index finger and a thumb of a hand, the needle is pulled down from between the index finger and the thumb of an operator, and when the needle enters the subcutaneous space for about 1cm, the needle head is tightly squeezed by two fingers (so that the phenomenon that injection is refluxed and oozed out of the skin to cause inaccurate injection dosage is avoided), and then the injection is started;
v) the solution is ready for use each time.
3.6) the specific steps of the administration of tetrathiomolybdate by intraperitoneal injection:
i) taking a healthy animal model (such as: mouse, rat), the body weight of which was weighed daily;
ii) dosage based on tetrathiomolybdate to be explored (e.g.: x [ mu ] mol/kg body weight) to prepare a tetrathiomolybdate solution with a certain concentration, and in order to facilitate perfusion quantification, the concentration of the tetrathiomolybdate solution is generally suitable for perfusing 1-10 [ mu ] L of the solution per gram of body weight;
iii) selecting a proper syringe needle according to the size of the animal, selecting a syringe with proper scales according to the injection quantity required, and carrying out intraperitoneal injection on the animal at regular time, wherein the experimental group is injected with a solution containing tetrathiomolybdate, and the control group is injected with a control solution not containing tetrathiomolybdate;
iv) during injection, the abdomen of the animal is prohibited upwards, the operator inserts the needle from the middle point of the connecting line of the hind limb and the midline of the abdomen to the animal body at an angle of 45 degrees from back to front, and when the operator feels that the needle penetrates the peritoneum, the injection is started;
v) the solution is ready for use each time.
3.7) the specific steps of intravenous administration of tetrathiomolybdate are as follows:
i) taking a healthy animal model (such as: mouse, rat), the body weight of which was weighed daily;
ii) based on the dosage of tetrathiomolybdate to be explored (e.g.: x mu mol/kg body weight) to prepare a tetrathiomolybdate physiological saline solution with a certain concentration, and in order to facilitate perfusion quantification, the concentration of the tetrathiomolybdate solution is generally suitable for perfusing 1-10 mu L of the solution per gram of body weight;
iii) selecting a proper syringe needle according to the size of the animal, selecting a syringe with proper scales according to the injection quantity required, and carrying out tail vein injection on the animal at regular time, wherein the experimental group is injected with a physiological saline solution containing tetrathiomolybdate, and the control group is injected with a physiological saline solution;
iv) during injection, the animal is restricted on a special restriction device for intravenous injection, an operator inserts a needle from the tail end 1/3 of the animal along the tail veins at two sides, and the injection is started after the operator feels that the needle enters the tail veins;
v) if no obvious resistance exists in the injection process, the needle is always in the tail vein, if obvious resistance is sensed, the needle is not in the tail vein, and the needle needs to be replaced at the tail end 2/3 of the tail vein on the other side or the tail vein on the same side;
vi) the solution is ready for use each time.
4) Tissue collection: after the administration period of 28 days is finished, carrying out centralized processing and dissection on experimental animals after bioelectrical impedance data is measured at 14:00, collecting each organ and weighing in detail, putting 4% paraformaldehyde into a part of tissues for subsequent histochemical analysis, and putting the rest part of tissues into liquid nitrogen for quick freezing for subsequent biochemical test;
5) the experimental data are statistically analyzed and then plotted into a graph (since the muscle-increasing effect of the present invention can be exerted by adding tetrathiomolybdate to drinking water, adding diet, making pills, making solutions for gastric administration or treating in different injection modes, only tetrathiomolybdate is added to daily diet of animals as a representative of comparative experimental data showing the muscle-increasing effect, see fig. 1 to 9 specifically).
In the above embodiment, the graph of the effect of tetrathiomolybdate on the bioelectrical impedance index of the experimental animal is shown in fig. 1, and as can be seen from fig. 1, the bioelectrical impedance index is significantly reduced by the tetrathiomolybdate group, and the smaller the index is, the higher the muscle proportion is, i.e., the tetrathiomolybdate increases the lean body mass proportion of the experimental animal.
In the above examples, the effect of tetrathiomolybdate administration on the weight indexes (skeletal muscle indexes) of gastrocnemius muscle (Rectus femoris) and Rectus femoris muscle (Percentage fibers) of experimental animals is shown in FIG. 2, and as can be seen from FIG. 2, tetrathiomolybdate in example 1 of the present invention significantly improves the weight indexes of gastrocnemius muscle and Rectus femoris muscle of experimental animals.
In the above embodiment, the effect of tetrathiomolybdate on the increase of total gastrocnemius protein capacity of the experimental animal is shown in fig. 3, and as can be seen from fig. 3, tetrathiomolybdate significantly increases the total gastrocnemius protein capacity of the experimental animal.
In the above examples, the effect of tetrathiomolybdate on the change in the cross-sectional area of the fibers of the gastrocnemius muscle of the experimental animal is shown in fig. 4, and as can be seen from fig. 4, tetrathiomolybdate increases the cross-sectional area of the fibers of the muscles typical of the H & E stained section of the gastrocnemius muscle of the experimental animal.
In the above embodiment, the effect of tetrathiomolybdate on the proportion of thicker muscle fibers in the gastrocnemius of the experimental animal is shown in fig. 5, and as can be seen from fig. 5, tetrathiomolybdate significantly increases the proportion of thicker muscle fibers in the gastrocnemius of the experimental animal.
In the above examples, the effect of tetrathiomolybdate on mRNA expression of a critical signal pathway for muscle synthesis in gastrocnemius muscle of experimental animals is shown in FIG. 6. As can be seen from FIG. 6, since mammalian rapamycin target of rapamycin, mTOR, is a key factor for regulating protein synthesis (Wang et al, physiology (Bethesda) 2006, 21, 362) and has a core regulatory role in muscle synthesis, this example explores the effect of tetrathiomolybdate on mRNA expression of mTOR itself, its upstream regulatory factor AKT [ also known as Protein Kinase B (PKB) ] and two downstream effector factors [ eukaryotic translation initiation factor 4E binding protein 1 (4E-BP 1) ] and ribosomal protein S6 kinase 1(ribosomal protein S6 kinase 1, 6kb1), the tetrathiomolybdate is found to obviously activate the mTOR myogenic signaling pathway of the gastrocnemius of the experimental animal, and the treatment of the tetrathiomolybdate can increase the mRNA expression of the related molecules of the mTOR myogenic signaling pathway of the gastrocnemius of the experimental animal.
In the above examples, a comparison graph of the effect of tetrathiomolybdate on the weight index of subcutaneous fat and visceral fat in experimental animals is shown in fig. 7, specifically, inguinal white fat and epididymal white fat are taken as examples; as can be seen from FIG. 7, tetrathiomolybdate decreased the weight index of subcutaneous fat and visceral fat in the experimental animals. These results show that: tetrathiomolybdate does not cause obesity when significantly enhanced muscle-building effects.
In the above examples, the effect of tetrathiomolybdate on the liver cell damage of the experimental animals is shown in fig. 8 and 9. As can be seen from FIGS. 8 and 9, neither serum glutamic-alanine Aminotransferase (ALT) nor aspartic acid Aminotransferase (AST) was elevated in the experimental animals after the tetrathiomolybdate treatment, indicating that the animals did not suffer from liver cell damage.
The above experimental results show that: tetrathiomolybdate can significantly increase muscle mass, significantly reduce fat mass, significantly increase muscle protein mass, significantly increase muscle fiber cross-sectional area, and can also fully activate mTOR muscle-increasing signal pathway; in addition, the spirit and behavior of the experimental animal are normal, the shape of the excrement is normal, and the liver function damage and other conditions are not generated in the process.
In correspondence with the above-mentioned mTOR myogenic signaling pathway activation, existing studies indicate that: the functional decline of the mTOR signaling pathway is a direct cause of sarcopenia and dystrophies (Evans et al, J Physiol 2021, Sakuma et al, Front Aging Neurosci 2014, 6, 230) and is directly associated with the activation of the muscle weakness (Chauhan et al, Neurosci Res 2013, 77, 102-, can compensate for energy metabolism deficiency in mitochondrial diseases and improve mitochondrial myopathy (Ji et al, Free Radic Biol Med 2015, 84, 161-170). Furthermore, during Muscle mass loss due to Cachexia, the activity of mTOR is inhibited (White et al, Am J Physiol Endocrinol metal 2013, 304, E1042-1052), prolonged use of mTOR inhibitors leads to Cachexia (Gyawali et al, Mol Clin Oncol 2016, 5, 641-646), tumor-induced Cachexia is also manifested as a decrease in mTOR activity (Nissinen et al, J Cachexia sarrophenocia Muscle 2018, 9, 514-529), and reactivation of mTOR improves the typical phenotype of Cachexia — Muscle loss (White et al, Am J Physiol Endocrinol metal 2013, 304, E1042-1052). Therefore, the tetrathiomolybdate can be applied to prepare related products or medicines for treating sarcopenia, muscular dystrophy, myasthenia, dermatomyositis, metabolic myopathy, rhabdomyolysis, congenital myopathy, concomitant myopathy, mitochondrial myopathy, cachexia and other diseases by activating the muscle increasing effect caused by the mTOR pathway.
This example provides the consistency of different administration methods of tetrathiomolybdate in augmenting muscle-related functions. In the embodiment, a healthy mouse model is adopted, the influence of different administration modes of tetrathiomolybdate on mouse muscle proliferation is explored, and the experimental result shows that: in the above examples, different administration methods (adding tetrathiomolybdate to the drinking water, adding to the diet, making into pills, or making into solutions and administering by different injection) all exerted similar muscle-increasing effects.
Example 2:
this example provides an illustrative example of the achievement of muscle-building function of tetrathiomolybdate at the animal cell level.
The influence of tetrathiomolybdate on the mouse myoblast differentiation is observed by adopting a C2C12 mouse myoblast model, and the change of each index of the model in the aspect of molecular biology is analyzed.
The experimental procedure was as follows:
1) cell culture: C2C12 mouse myoblasts were diluted to 1X 10 with medium containing 10% fetal bovine serum (DMEM high-glucose) 5 Cells/ml, seeded in 6-well plates at 37 ℃ in 5% CO 2 Culturing under the environment; when the cell density reached about 80-85%, the wells were purged of medium and supplemented with medium containing 2% horse serum (DMEM high glucose) for induction of myotube differentiation; wherein, the experimental group is added with tetrathiomolybdate dissolved by DMSO (since the previous experiment shows that the concentration of tetrathiomolybdate in a culture medium is 1 nmol/L-200 mmol/L, the tetrathiomolybdate has influence on the function of C2C12 cells, in the experimental process, tetrathiomolybdate solution with specific concentration can be added according to the experimental purpose), and the control group is added with DMSO with corresponding amount;
2) differentiation observation: during the differentiation process of 0-7 days, photographing every 24 hours to record the cell differentiation condition of the experimental group and the control group;
3) cell collection: collecting mRNA every 24 hours during differentiation of 0-7 days for analyzing expression change of myoblast differentiation related gene;
4) the above experimental data were statistically analyzed and plotted (see FIGS. 10-12).
In the above examples, the effect of tetrathiomolybdate treatment on the differentiation rate of C2C12 cells is shown in FIG. 10, and it can be seen from FIG. 10 that tetrathiomolybdate administration significantly accelerates the differentiation rate of C2C12 cells.
In the above examples, the effect of tetrathiomolybdate treatment on myogenin (MyoG) mRNA expression induced differentiation of C2C12 cells as shown in fig. 11, it can be seen from fig. 11 that the expression of myogenin (MyoG) mRNA induced differentiation of C2C12 cells is significantly increased after tetrathiomolybdate administration.
In the above examples, the effect of tetrathiomolybdate treatment on the expression of myoglobulin (MyHc) mRNA formed in myotubes of C2C12 cells was shown in fig. 12, which shows that the expression of myoglobulin (MyHc) mRNA formed in myotubes of C2C12 cells was significantly increased after tetrathiomolybdate treatment, as shown in fig. 12.
The above experimental results show that: tetrathiomolybdate promotes myoblast differentiation in C2C12 mice, increases myotube formation in C2C12 cells, and increases myogenin (MyoG) and myosin (MyHc) mRNA expression.
Example 3:
this example provides an example of the functional demonstration of tetrathiomolybdate in improving animal athletic ability and learning and memory ability.
The performance of the mouse model in the Morris water maze experiment after administration of tetrathiomolybdate was observed using a healthy mouse model, and the change in each index representing the motor ability and learning and memory ability of the mouse was analyzed (see fig. 13 to 15).
As can be seen from FIG. 13, the tetrathiomolybdate treatment in this example increased the swimming speed of the mice, the faster the speed, the better the locomotor ability of the mice.
As can be seen from fig. 14 and 15, the tetrathiomolybdate treatment in this example reduced the latency before the mice found the platform and increased the number of times the mice passed through the hidden platform, both of which indicate an enhanced learning and memory capacity of the mice, indicating that the tetrathiomolybdate treatment has at least no damage to the nervous system.
The existing theoretical research shows that: muscles, in addition to the motor and metabolic organs, are also endocrine organs which, by secreting various endocrine factors, have important regulatory effects on the metabolism of the body, while muscle mass is the determining factor for their function (Giudice et al, Curr Opin Pharmacol 2017, 34, 49-55, Iizuka et al, J Pharmacol Sci 2014, 125-. It can thus be seen that: maintaining stable muscle mass is the basis for maintaining the functions of muscle such as strength output, endocrine, metabolism regulation and the like. The above experiments have verified from the enhancement of exercise capacity that "tetrathiomolybdate can enhance exercise function by increasing muscle mass", and thus, in combination with existing research, it can be found that: the increase of the muscle mass of the mice promoted by the thiomolybdate can enhance the endocrine function and the metabolic regulation function of the mice, can obviously improve the motor ability of the mice and has no side effect on the nervous system. .
Example 4:
this example provides an active unit of tetrathiomolybdate that performs a muscle building function.
The effect of two tetrathiomolybdates (ammonium tetrathiomolybdate, choline tetrathiomolybdate) administered at the same molar concentration or the same mass concentration on proliferation and differentiation of C2C12 myoblasts was observed using the C2C12 mouse myoblast model (see fig. 16).
The experimental results show that: the two tetrathiomolybdates were administered at the same molar concentrations and had a consistent degree of promotion of C2C12 myoblast proliferation and differentiation; the two tetrathiomolybdates were administered at the same mass concentration, which did not promote the proliferation and differentiation of C2C12 myoblasts to the same extent. Thus, the muscle-building efficacy of tetrathiomolybdate is only associated with tetrathiomolybdate ion (MoS) 4 2- ) The molar concentrations of (a) and (b) are directly related, while the mass fractions of the different cations bound to them have no significant effect on the experimental effect, which indicates that: tetrathiomolybdate ion (MoS) 4 2- ) Is an active unit of tetrathiomolybdate which plays a muscle-increasing function.
Example 5:
this example provides a dosage range and safe concentrations of tetrathiomolybdate for its muscle-building effect.
After treatment with C2C12 mouse myoblasts and healthy mouse model by adding tetrathiomolybdate at different concentrations, it was found experimentally that: under the condition of low 1nmol/L, tetrathiomolybdate still has the effect on the function of C2C12 cells; under the condition of supplying 768 mu mol of tetrathiomolybdate per kilogram of body weight of the mouse (768 mu mol/kg of body weight), the muscle growth of the mouse can be still promoted; and none of the above doses showed significant toxicity.
Claims (10)
1. The tetrathiomolybdate is applied to preparing medicines capable of realizing muscle increasing and muscle function improving.
2. The use according to claim 1, for the preparation of a medicament for improving exercise performance, preventing or treating disorders associated with the muscular system.
3. Use according to claims 1 and 2, characterized in that said tetrathiomolybdate has the general molecular formula X + MoS 4 2- Y + The structural formula is as follows:
wherein the positions of the ionic bonds of the 4 sulfide ions are interchangeable; x + And Y + Are the same or different cations.
4. Use according to claim 3, wherein the cation is one that dissociates in solution to produce MoS 4 2- Or can be enzymatically hydrolyzed in a biological system to produce MoS 4 2- Inorganic cations and/or organic cations.
5. Use according to claim 4, wherein the inorganic cations comprise Na + 、K + 、NH 4 + At least one of (a); the organic cation comprises at least one of amine ions and choline ions.
6. Use according to claim 5, wherein the inorganic cation comprises NH 4 + (ii) a The organic cation comprises choline ion.
7. The use of any one of claims 1 to 6, wherein said augmenting muscle comprises at least one of promoting proliferation of myoblasts, promoting differentiation of myoblasts into muscle cells, increasing muscle mass in the body;
the improvement of the muscle function comprises at least one of the conditions of enhancing the stretching function of the muscle, enhancing the motor function of the muscle, improving the endocrine function of the muscle, improving the metabolic function of the muscle and enhancing the regulating capacity of the muscle to blood sugar;
the muscle system related diseases include at least one of myasthenia, sarcopenia, dermatomyositis, progressive muscular dystrophy, congenital myopathy, metabolic myopathy, infectious myopathy, concomitant myopathy, mitochondrial myopathy, rhabdomyolysis and cachexia.
8. The use according to any one of claims 1 to 6, wherein the tetrathiomolybdate is prepared as a 1nmol/L to 200mmol/L or 1nmol/Kg to 200mmol/Kg nutritional or pharmaceutical solution that can be orally administered, drunk or injected, or as a solid nutritional or pharmaceutical composition.
9. The use of claim 8, wherein the nutritional solution, pharmaceutical solution, nutritional composition or pharmaceutical composition comprises at least one of a pharmaceutically acceptable diluent, excipient, adjuvant or existing muscle building agent.
10. The use according to any one of claims 1 to 6, wherein the tetrathiomolybdate is used for preparing a medicament which does not cause obesity and/or has no liver injury toxicity and/or no nervous system injury.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1266817A (en) * | 1999-09-29 | 2000-09-20 | 中国科学院兰州化学物理研究所 | Tetrathiomolybdate, and its preparing process and application |
| CN1684678A (en) * | 2002-07-23 | 2005-10-19 | 阿特努奥恩公司 | Thiomolybdate analogues and uses thereof |
| AU2007201085A1 (en) * | 2002-05-24 | 2007-04-05 | The Regents Of The University Of Michigan | Copper lowering treatment of inflammatory and fibrotic diseases |
| JP2008106006A (en) * | 2006-10-26 | 2008-05-08 | Univ Nihon | Treating agent for amyotrophic lateral sclerosis |
| EP2578221A1 (en) * | 2011-10-04 | 2013-04-10 | Magnus Intellectual Property Ltd. | The therapeutic use of tetrathiomolybdate |
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| US10478455B2 (en) * | 2010-03-30 | 2019-11-19 | Ucl Business Ltd | Therapeutic use of tetrathiomolybdate |
| US11419832B2 (en) * | 2017-12-04 | 2022-08-23 | Alexion Pharmaceuticals, Inc. | Bis-choline tetrathiomolybdate for treating Wilson Disease |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1266817A (en) * | 1999-09-29 | 2000-09-20 | 中国科学院兰州化学物理研究所 | Tetrathiomolybdate, and its preparing process and application |
| AU2007201085A1 (en) * | 2002-05-24 | 2007-04-05 | The Regents Of The University Of Michigan | Copper lowering treatment of inflammatory and fibrotic diseases |
| CN1684678A (en) * | 2002-07-23 | 2005-10-19 | 阿特努奥恩公司 | Thiomolybdate analogues and uses thereof |
| JP2008106006A (en) * | 2006-10-26 | 2008-05-08 | Univ Nihon | Treating agent for amyotrophic lateral sclerosis |
| EP2578221A1 (en) * | 2011-10-04 | 2013-04-10 | Magnus Intellectual Property Ltd. | The therapeutic use of tetrathiomolybdate |
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