MOTS-c reduces myostatin and muscle atrophy signaling.

Obesity and type 2 diabetes are metabolic diseases, often associated with sarcopenia and muscle dysfunction. MOTS-c, a mitochondrial-derived peptide, acts as a systemic hormone and has been implicated in metabolic homeostasis. Although MOTS-c improves insulin sensitivity in skeletal muscle, whether MOTS-c impacts muscle atrophy is not known. Myostatin is a negative regulator of skeletal muscle mass and also one of the possible mediators of insulin resistance-induced skeletal muscle wasting. Interestingly, we found that plasma MOTS-c levels are inversely correlated with myostatin levels in human subjects. We further demonstrated that MOTS-c prevents palmitic acid-induced atrophy in differentiated C2C12 myotubes, whereas MOTS-c administration decreased myostatin levels in plasma in diet-induced obese mice. By elevating AKT phosphorylation, MOTS-c inhibits the activity of an upstream transcription factor for myostatin and other muscle wasting genes, FOXO1. MOTS-c increases mTORC2 and inhibits PTEN activity, which modulates AKT phosphorylation. Further upstream, MOTS-c increases CK2 activity, which leads to PTEN inhibition. These results suggest that through inhibition of myostatin, MOTS-c could be a potential therapy for insulin resistance-induced skeletal muscle atrophy as well as other muscle wasting phenotypes including sarcopenia.NEW & NOTEWORTHY MOTS-c, a mitochondrial-derived peptide reduces high-fat-diet-induced muscle atrophy signaling by reducing myostatin expression. The CK2-PTEN-mTORC2-AKT-FOXO1 pathways play key roles in MOTS-c action on myostatin expression.

IGF1 does not overcome sexual dimorphism of body and muscle size in Mstn-/- mice.

Insulin-like growth factor-1 (IGF1) is crucial for regulating post-natal growth and, along with myostatin (MSTN), regulates muscle size. Here, we sought to clarify the roles of these two genes in regulating sexually dimorphic growth of body and muscle mass. In the first study, we established that Igf1 mRNA was increased to a greater extent and Igf1 receptor mRNA increased earlier in male, than in female, gastrocnemius muscles during the rapid phase of growth (from 2 to 6 weeks) were unchanged, thereafter, to 32 weeks of age in WT mice (P < 0.001). In the second study, we sought to determine if supplemental IGF1 could overcome the sexual dimorphism of muscle and body mass, when myostatin is absent. We crossed myostatin null (Mstn-/-) mice with mice over-expressing Igf1 in skeletal muscle (Igf1+) to generate six genotypes; control (Mstn+/+), Mstn+/-, Mstn-/-, Mstn+/+:Igf1+, Mstn+/-:Igf1+ and Mstn-/-:Igf1+ (n = 8 per genotype and sex). In both sexes, body mass at 12 weeks was increased by at least 1.6-fold and muscle mass by at least 3-fold in Mstn-/-:Igf1+ compared with Mstn+/+ mice (P < 0.001). The abundance of AKT was increased in muscles of mice transgenic for Mstn, while phosphorylation of AKTS473 was increased in both male and female mice transgenic for Igf1+. The ratio of phosphorylated to total AKT was 1.9-fold greater in male mice (P < 0.001). Thus, despite increased growth of skeletal muscle and body size when myostatin was absent and IGF1 was in excess, sexual dimorphism persisted, an effect consistent with greater IGF1-induced activation of AKT in skeletal muscles of males.

Muscle Atrophy After ACL Injury: Implications for Clinical Practice.

CONTEXT: Distinct from the muscle atrophy that develops from inactivity or disuse, atrophy that occurs after traumatic joint injury continues despite the patient being actively engaged in exercise. Recognizing the multitude of factors and cascade of events that are present and negatively influence the regulation of muscle mass after traumatic joint injury will likely enable clinicians to design more effective treatment strategies. To provide sports medicine practitioners with the best strategies to optimize muscle mass, the purpose of this clinical review is to discuss the predominant mechanisms that control muscle atrophy for disuse and posttraumatic scenarios, and to highlight how they differ. EVIDENCE ACQUISITION: Articles that reported on disuse atrophy and muscle atrophy after traumatic joint injury were collected from peer-reviewed sources available on PubMed (2000 through December 2019). Search terms included the following: disuse muscle atrophy OR disuse muscle mass OR anterior cruciate ligament OR ACL AND mechanism OR muscle loss OR atrophy OR neurological disruption OR rehabilitation OR exercise. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 5. RESULTS: We highlight that (1) muscle atrophy after traumatic joint injury is due to a broad range of atrophy-inducing factors that are resistant to standard resistance exercises and need to be effectively targeted with treatments and (2) neurological disruptions after traumatic joint injury uncouple the nervous system from muscle tissue, contributing to a more complex manifestation of muscle loss as well as degraded tissue quality. CONCLUSION: Atrophy occurring after traumatic joint injury is distinctly different from the muscle atrophy that develops from disuse and is likely due to the broad range of atrophy-inducing factors that are present after injury. Clinicians must challenge the standard prescriptive approach to combating muscle atrophy from simply prescribing physical activity to targeting the neurophysiological origins of muscle atrophy after traumatic joint injury.

Effects of whole-body cryotherapy on 25-hydroxyvitamin D, irisin, myostatin, and interleukin-6 levels in healthy young men of different fitness levels.

Skeletal muscle and adipose tissue play an important role in maintaining metabolic homeostasis and thermogenesis. We aimed to investigate the effects of single and repeated exposure to whole-body cryotherapy in volunteers with different physical fitness levels on 25-hydroxyvitamin D (25(OH)D) and myokines. The study included 22 healthy male volunteers (mean age: 21 ± 1.17 years), who underwent 10 consecutive sessions in a cryogenic chamber once daily (3 minutes, -110 °C). Blood samples were collected before and 30 minutes and 24 hours after the first and last cryotherapy sessions. Prior to treatment, body composition and physical fitness levels were measured. After 10 cryotherapy treatments, significant changes were found in myostatin concentrations in the low physical fitness level (LPhL) group. The 25(OH)D levels were increased in the high physical fitness level (HPhL) group and decreased in the LPhL group. The HPhL group had significant changes in the level of high-sensitivity interleukin-6 after the first treatment. The LPhL group had significant changes in 25(OH)D, irisin, and myostatin levels after the tenth treatment. Our data demonstrated that in healthy young men, cryotherapy affects 25(OH)D levels, but they were small and transient. The body's response to a series of 10 cryotherapy treatments is modified by physical fitness level.

Mutation in myostatin 3'UTR promotes C2C12 myoblast proliferation and differentiation by blocking the translation of MSTN.

The point mutation in myostatin (MSTN) can produce the Texel sheep double muscle phenotype. However, whether other species have the same mode of action as MSTN and whether breeding materials can be obtained through cross-species genetic editing remain unclear. The mutation in the mouse MSTN 3'UTR could create a target site for mmu-miR-1/206, as verified by the dual luciferase reporter system. A C2C12 cell model with the mutation in MSTN 3'UTR was constructed using CRISPR/Cas9 gene editing. Then, the mRNA and protein expression of MSTN was analyzed in the mutant C2C12 cell model. Results revealed that the mutation blocked the translational level of MSTN. By inhibiting mmu-mir-206, low expression of MSTN protein in mutant C2C12 cell can be rescued. Furthermore, the proliferation and differentiation abilities of the mutant C2C12 cell model were tested by RT-PCR, CCK8 analysis, EDU (5-ethynyl-2'-deoxyuridine) proliferation analysis, immunofluorescence analysis, Western blot, and myotube fusion statistics. This study may serve as a reference for elucidating the function and molecular mechanism of MSTN and as a foundation for accurate breeding improvement.

Generation of myostatin-knockout chickens mediated by D10A-Cas9 nickase.

Many studies have been conducted to improve economically important livestock traits such as feed efficiency and muscle growth. Genome editing technologies represent a major advancement for both basic research and agronomic biotechnology development. The clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technical platform is a powerful tool used to engineer specific targeted loci. However, the potential occurrence of off-target effects, including the cleavage of unintended targets, limits the practical applications of Cas9-mediated genome editing. In this study, to minimize the off-target effects of this technology, we utilized D10A-Cas9 nickase to generate myostatin-knockout (MSTN KO) chickens via primordial germ cells. D10A-Cas9 nickase (Cas9n)-mediated MSTN KO chickens exhibited significantly larger skeletal muscles in the breast and leg. Degrees of skeletal muscle hypertrophy and hyperplasia induced by myostatin deletion differed by sex and muscle type. The abdominal fat deposition was dramatically lower in MSTN KO chickens than in wild-type chickens. Our results demonstrate that the D10A-Cas9 technical platform can facilitate precise and efficient targeted genome engineering and may broaden the range of applications for genome-edited chickens in practical industrialization and as animal models of human diseases.

Myostatin dysfunction is associated with lower physical activity and reduced improvements in glucose tolerance in response to caloric restriction in Berlin high mice.

Myostatin is an inhibitor of skeletal muscle growth and might be involved in adaptations to caloric restriction (CR). We compared responses to 12-week 30% CR in male mice of Berlin high strain with myostatin dysfunction (BEH) and wild-type myostatin (BEH+/+). BEH mice were heavier than BEH+/+ mice (58.8 ±â€¯2.0 versus 53.1 ±â€¯2.7 g, p < 0.001), had 1.8-fold greater hind limb muscle mass and were less (p < 0.05) physically active when fed ad libitum. After CR, BEH and BEH+/+ strains experienced similar weight loss (24.7 ±â€¯5.7 versus 20.6 ±â€¯6.5%, p > 0.05, respectively) and decreases (p < 0.001) in plasma IGF-1 and total cholesterol, but loss of hind limb muscle mass was greater (p < 0.001) in BEH mice than BEH+/+ mice. BEH mice had better (p < 0.001) glucose tolerance and showed smaller (p < 0.05) improvements of it than BEH+/+ mice after CR (1038.2 ±â€¯174.7 versus 744.4 ±â€¯95.8 glucose mM× 120 min, p < 0.01 for BEH; 1365.8 ±â€¯218.5 versus 831.5 ±â€¯134.4 glucose mM ×120 min, p < 0.001, for BEH+/+, respectively). In summary, myostatin dysfunction is associated with muscle hypertrophy and high glucose tolerance, but greater muscle wasting and smaller improvements in glucose tolerance in response to CR.

Myostatin Upregulation in Patients in the Chronic Phase of Severe Burn Injury Leads to Muscle Cell Catabolism.

BACKGROUND: Burn injury leads to a hypercatabolic response and ultimately muscle wasting with drastic implications for recovery of bodily functions, patient's quality of life (QoL), and long-term survival. Several treatment options target the body's initial stress response, but pharmacological approaches to specifically address muscle protein metabolism have only been poorly investigated. OBJECTIVE: The aim of this study was to assess the role of myostatin and follistatin in burn injury and its possible implications in muscle wasting syndrome. METHODS: We harvested serum from male patients within 48 h and again 9-12 months after severe burn injury (>20% of total body surface area). By means of myoblast cultures, immunohistochemistry, immunoblotting, and scratch assay, the role of myostatin and its implications in post-burn muscle metabolism and myoblast proliferation and differentiation was analyzed. RESULTS: We were able to show increased proliferative and myogenic capacity, decreased myostatin, decreased SMAD 2/3, and elevated follistatin concentrations in human skeletal myoblast cultures with serum conditioned medium of patients in the acute phase of burn injury and conversely a reversed situation in patients in the chronic phase of burn injury. Thus, there is a biphasic response to burn trauma, initiated by an anabolic state and followed by long-term hypercatabolism. CONCLUSION: We conclude that the myostatin signaling pathway plays an important regulative role in burn-associated muscle wasting and that blockade of myostatin could prove to be a valuable treatment approach improving the rehabilitation process, QoL, and long-term survival after severe burn injury.

Specific inhibition of myostatin activation is beneficial in mouse models of SMA therapy.

Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by loss of α-motor neurons, leading to profound skeletal muscle atrophy. Patients also suffer from decreased bone mineral density and increased fracture risk. The majority of treatments for SMA, approved or in clinic trials, focus on addressing the underlying cause of disease, insufficient production of full-length SMN protein. While restoration of SMN has resulted in improvements in functional measures, significant deficits remain in both mice and SMA patients following treatment. Motor function in SMA patients may be additionally improved by targeting skeletal muscle to reduce atrophy and improve muscle strength. Inhibition of myostatin, a negative regulator of muscle mass, offers a promising approach to increase muscle function in SMA patients. Here we demonstrate that muSRK-015P, a monoclonal antibody which specifically inhibits myostatin activation, effectively increases muscle mass and function in two variants of the pharmacological mouse model of SMA in which pharmacologic restoration of SMN has taken place either 1 or 24 days after birth to reflect early or later therapeutic intervention. Additionally, muSRK-015P treatment improves the cortical and trabecular bone phenotypes in these mice. These data indicate that preventing myostatin activation has therapeutic potential in addressing muscle and bone deficiencies in SMA patients. An optimized variant of SRK-015P, SRK-015, is currently in clinical development for treatment of SMA.

Effect of myostatin inhibitor (myostatin pro-peptide) microinjection on in vitro maturation and subsequent early developmental stages of buffalo embryo.

Expression of myostatin (MSTN, also known as growth differentiation factor 8, GDF8) was recently detected in cumulus-oocytes complexes (COCs), however little is known about its role in in vitro maturation (IVM) and fertilization (IVF) in large animals. Therefore, this study was designed to investigate the effect of MSTN inhibition on IVM of buffalo oocytes through investigation of IVM efficiency and expression of some specific genes in COCs from IVM till subsequent developmental stages following IVF. To reach this goal, we prepared a construct of adeno-associated virus (AAV) carrying MSTN pro-peptides (AAV-MSTNP) to inhibit MSTN. Over-expression of MSTNP was verified by upregulated expression of MSTNP and downregulated expression of the TGFß receptor ActRIIb, the TGFß signal transducer SMAD2 in COCs using qPCR. Microinjection of AAV-MSTNP to oocytes before IVM yielded a significant decrease in maturation rate as revealed by less cumulus cells expansion, fewer oocytes reaching metaphase II, and downregulation of cumulus expansion-related genes pentraxin 3 (Ptx3) and prostaglandin-endoperoxide synthase 2 (Ptgs2) as compared to the control and vehicle groups. These changes were also accompanied by elevated intracellular reactive oxygen species (ROS), upregulated expression of the apoptotic Bax gene, reduced antioxidant enzymes (SOD, CAT, GPX) activities, and downregulated expression of the antioxidant gene nuclear factor erythroid 2 like 2 (Nrf2), and the anti-apoptotic gene Bcl2 in COCs after IVM. Overexpression of MSTN inhibitor, MSTNP, also inhibited GDF9 and BMP15 genes expression in COCs. Additionally, both the fertilization efficiency and cleavage and blastocyst rates were significantly lower in MSTNP group than in the control and vehicle groups. The obtained data suggest an important role for MSTN during IVM and the subsequent developmental stages probably through, at least in part, inhibition of ROS production and apoptosis and modulation of IVM-related gene expression in COCs.

[Do Myokines Have Potential as Exercise Mimetics?]

　Exercise is generally considered to have health benefits for the body, although its beneficial mechanisms have not been fully elucidated. Recent progressive research suggests that myokines, bioactive substances secreted from skeletal muscle, play an important role in mediating the benefits of exercise. There are three types of myokines in terms of the muscular secretion mechanism: those in which the secretion is promoted by stimulation, such as irisin, interleukin (IL)-6, and IL-15; those whose secretion is constitutive, such as thioredoxin, glutaredoxin, and peroxiredoxin; and those whose secretion is suppressed by stimulation, such as by a macrophage migration inhibitory factor. Although dozens of myokines have been reported, their physiological roles are not well understood. Therefore, there currently exists no advanced drug discovery research specifically targeting myokines, with the exception of Myostatin. Myostatin was discovered as a negative regulator of muscle growth. Myostatin is secreted from muscle cells as a myokine; it signals via an activin type IIB receptor in an autocrine manner, and regulates gene expressions involved in myogenesis. Given the studies to date that have been conducted on the utilization of myostatin inhibitors for the treatment of muscle weakness, including cachexia and sarcopenia, other myokines may also be new potential drug targets.

Effect of Myostatin SNP on muscle fiber properties in male Thoroughbred horses during training period.

Variants of the Myostatin gene have been shown to have an influence on muscle hypertrophy phenotypes in a wide range of mammalian species. Recently, a Thoroughbred horse with a C-Allele at the g.66493737C/T single-nucleotide polymorphism (SNP) has been reported to be suited to short-distance racing. In this study, we examined the effect of the Myostatin SNP on muscle fiber properties in young Thoroughbred horses during a training period. To investigate the effect of the Myostatin SNP on muscle fiber before training, several mRNA expressions were relatively quantified in biopsy samples from the middle gluteal muscle of 27 untrained male Thoroughbred horses (1.5 years old) using real-time RT-PCR analysis. The remaining muscle samples were used for immunohistochemical analysis to determine the population and area of each fiber type. All measurements were revaluated in biopsy samples of the same horses after a 5-month period of conventional training. Although the expressions of Myostatin mRNA decreased in all SNP genotypes, a significant decrease was found in only the C/C genotype after training. While, expression of VEGFa, PGC1α, and SDHa mRNAs, which relate to the biogenesis of mitochondria and capillaries, was significantly higher (54-82%) in the T/T than the C/C genotypes after training. It is suggested that hypertrophy of muscle fiber is directly associated with a decrease in Myostatin mRNA expression in the C/C genotype, and that increased expressions of VEGFa, PGC1α, and SDHa in the T/T genotype might be indirectly caused by the Myostatin SNP.

Establishment and phenotypic analysis of an Mstn knockout rat.

Myostatin (Mstn) is an inhibitor of myogenesis, regulating the number and size of skeletal myocytes. In addition to its myogenic regulatory function, Mstn plays important roles in the development of adipose tissues and in metabolism. In the present study, an Mstn knockout rat model was generated using the zinc finger nuclease (ZFN) technique in order to further investigate the function and mechanism of Mstn in metabolism. The knockout possesses a frame shift mutation resulting in an early termination codon and a truncated peptide of 109 amino acids rather than the full 376 amino acids. The absence of detectable mRNA confirmed successful knockout of Mstn. Relative to wild-type (WT) littermates, Knockout (KO) rats exhibited significantly greater body weight, body circumference, and muscle mass. However, no significant differences in grip force was observed, indicating that Mstn deletion results in greater muscle mass but not greater muscle fiber strength. Additionally, KO rats were found to possess less body fat relative to WT littermates, which is consistent with previous studies in mice and cattle. The aforementioned results indicate that Mstn knockout increases muscle mass while decreasing fat content, leading to observed increases in body weight and body circumference. The Mstn knockout rat model provides a novel means to study the role of Mstn in metabolism and Mstn-related muscle hypertrophy.

Biochemistry and Biology of GDF11 and Myostatin: Similarities, Differences, and Questions for Future Investigation.

Growth differentiation factor 11 (GDF11) and myostatin (or GDF8) are closely related members of the transforming growth factor ß superfamily and are often perceived to serve similar or overlapping roles. Yet, despite commonalities in protein sequence, receptor utilization and signaling, accumulating evidence suggests that these 2 ligands can have distinct functions in many situations. GDF11 is essential for mammalian development and has been suggested to regulate aging of multiple tissues, whereas myostatin is a well-described negative regulator of postnatal skeletal and cardiac muscle mass and modulates metabolic processes. In this review, we discuss the biochemical regulation of GDF11 and myostatin and their functions in the heart, skeletal muscle, and brain. We also highlight recent clinical findings with respect to a potential role for GDF11 and/or myostatin in humans with heart disease. Finally, we address key outstanding questions related to GDF11 and myostatin dynamics and signaling during development, growth, and aging.

Is Growth Differentiation Factor 11 a Realistic Therapeutic for Aging-Dependent Muscle Defects?

This "Controversies in Cardiovascular Research" article evaluates the evidence for and against the hypothesis that the circulating blood level of growth differentiation factor 11 (GDF11) decreases in old age and that restoring normal GDF11 levels in old animals rejuvenates their skeletal muscle and reverses pathological cardiac hypertrophy and cardiac dysfunction. Studies supporting the original GDF11 hypothesis in skeletal and cardiac muscle have not been validated by several independent groups. These new studies have either found no effects of restoring normal GDF11 levels on cardiac structure and function or have shown that increasing GDF11 or its closely related family member growth differentiation factor 8 actually impairs skeletal muscle repair in old animals. One possible explanation for what seems to be mutually exclusive findings is that the original reagent used to measure GDF11 levels also detected many other molecules so that age-dependent changes in GDF11 are still not well known. The more important issue is whether increasing blood [GDF11] repairs old skeletal muscle and reverses age-related cardiac pathologies. There are substantial new and existing data showing that GDF8/11 can exacerbate rather than rejuvenate skeletal muscle injury in old animals. There is also new evidence disputing the idea that there is pathological hypertrophy in old C57bl6 mice and that GDF11 therapy can reverse cardiac pathologies. Finally, high [GDF11] causes reductions in body and heart weight in both young and old animals, suggestive of a cachexia effect. Our conclusion is that elevating blood levels of GDF11 in the aged might cause more harm than good.

Anti-myostatin antibody increases muscle mass and strength and improves insulin sensitivity in old mice.

Sarcopenia, or skeletal muscle atrophy, is a debilitating comorbidity of many physiological and pathophysiological processes, including normal aging. There are no approved therapies for sarcopenia, but the antihypertrophic myokine myostatin is a potential therapeutic target. Here, we show that treatment of young and old mice with an anti-myostatin antibody (ATA 842) for 4 wk increased muscle mass and muscle strength in both groups. Furthermore, ATA 842 treatment also increased insulin-stimulated whole body glucose metabolism in old mice, which could be attributed to increased insulin-stimulated skeletal muscle glucose uptake as measured by a hyperinsulinemic-euglycemic clamp. Taken together, these studies provide support for pharmacological inhibition of myostatin as a potential therapeutic approach for age-related sarcopenia and metabolic disease.

Influence of rice whole-crop silage diet on growth performance, carcass and meat characteristics and muscle-related gene expression in Japanese Black steers.

The present study investigated the influence of a diet largely comprising rice whole-crop silage (rWCS) on growth performance, carcass and meat characteristics, and expression of genes involved in muscle growth of Japanese Black steers. Steers were randomly separated into rWCS-fed (rWCS ad libitum and restricted feeding of concentrate) and concentrate-fed groups. Total digestible nutrient intake and daily gain (DG) decreased in rWCS-fed steers in comparison with concentrate-fed steers, whereas dressed carcass weight and final body weight did not significantly differ between the groups. Decreases in drip loss in the muscle of rWCS-fed steers may be caused by α-tocopherol and ß-carotene in muscle. Feeding large amounts of rWCS to steers may maintain quantitative productivity of beef steers equally to a concentrate-based diet, and improve the qualitative productivity. Results of gene expression suggest that activation of skeletal muscle growth in rWCS-fed steers may occur at the late fattening period owing to a decrease in myostatin and increase in myosin heavy chain gene expression. Preadipocyte factor-1 and myostatin genes may be strongly involved in the control of lipid accumulation. This rearing system would allow beef production to switch to rWCS-based diets from concentrate-based diets.

Myostatin deficiency partially rescues the bone phenotype of osteogenesis imperfecta model mice.

UNLABELLED: Mice with osteogenesis imperfecta (+/oim), a disorder of bone fragility, were bred to mice with muscle over growth to test whether increasing muscle mass genetically would improve bone quality and strength. The results demonstrate that femora from mice carrying both mutations have greater mechanical integrity than their +/oim littermates. INTRODUCTION: Osteogenesis imperfecta is a heritable connective tissue disorder due primarily to mutations in the type I collagen genes resulting in skeletal deformity and fragility. Currently, there is no cure, and therapeutic strategies encompass the use of antiresorptive pharmaceuticals and surgical bracing, with limited success and significant potential for adverse effects. Bone, a mechanosensing organ, can respond to high mechanical loads by increasing new bone formation and altering bone geometry to withstand increased forces. Skeletal muscle is a major source of physiological loading on bone, and bone strength is proportional to muscle mass. METHODS: To test the hypothesis that congenic increases in muscle mass in the osteogenesis imperfecta murine model mouse (oim) will improve their compromised bone quality and strength, heterozygous (+/oim) mice were bred to mice deficient in myostatin (+/mstn), a negative regulator of muscle growth. The resulting adult offspring were evaluated for hindlimb muscle mass, and bone microarchitecture, physiochemistry, and biomechanical integrity. RESULTS: +/oim mice deficient in myostatin (+/mstn +/oim) were generated and demonstrated that myostatin deficiency increased body weight, muscle mass, and biomechanical strength in +/mstn +/oim mice as compared to +/oim mice. Additionally, myostatin deficiency altered the physiochemical properties of the +/oim bone but did not alter bone remodeling. CONCLUSIONS: Myostatin deficiency partially improved the reduced femoral bone biomechanical strength of adult +/oim mice by increasing muscle mass with concomitant improvements in bone microarchitecture and physiochemical properties.