The central role of myostatin in skeletal muscle and whole body homeostasis

Myostatin is a powerful negative regulator of skeletal muscle mass in mammalian species. It plays a key role in skeletal muscle homeostasis and has now been well described since its discovery. Myostatin is capable of inducing muscle atrophy via its inhibition of myoblast proliferation, increasing ubiquitin-proteasomal activity and downregulating activity of the IGF-Akt pathway. These well-recognized effects are seen in multiple atrophy causing situations, including injury, diseases such as cachexia, disuse and space flight, demonstrating the importance of the myostatin signalling mechanism. Based on this central role, significant work has been pursued to inhibit myostatin's actions in vivo. Importantly, several new studies have uncovered roles for myostatin distinct from skeletal muscle size. Myostatin has been suggested to play a role in cardiomyocyte homeostasis, glucose metabolism and adipocyte proliferation, all of which are examined in detail below. Based on these effects, myostatin inhibition has potential to be widely utilized in many Western diseases such as chronic obstructive pulmonary disease, type II diabetes and obesity. However, if myostatin inhibitors are to successfully translate from bench-top to bedside in the near future, awareness must be raised on these non-traditional effects of myostatin away from skeletal muscle. Indeed, further research into these novel areas is required.     

miRNAs在骨骼肌损伤修复过程中的调控作用

不合理的运动方式经常会引起骨骼肌损伤,骨骼肌损伤后,成体生肌性干细胞(主要是卫星细胞)被激活,进而增殖分化,与原来肌纤维融合完成修复过程。miRNAs是一种在后转录水平调节基因表达的非编码RNAs,在骨骼肌损伤与修复过程中主要通过靶向抑制一些转录因子、转录激活途径关键酶、细胞通讯连接重要蛋白以及各种信号通路中关键蛋白的翻译而发挥调控作用。为了更好地了解miRNAs在骨骼肌损伤修复过程中的作用,本文通过对miRNAs在骨骼肌损伤与修复过程中卫星细胞不同生物学状态以及信号通路等方面的作用和研究现状做一综述。     

The influence of skeletal muscle on the regulation of liver:body mass and liver regeneration

The relationship between liver and body mass is exemplified by the precision with which the liver:body mass ratio is restored after partial hepatic resection. Nevertheless, the compartments, against which liver mass is so exquisitely regulated, currently remain undefined. In the studies reported here, we investigated the role of skeletal muscle mass in the regulation of liver:body mass ratio and liver regeneration via the analysis of myostatin-null mice, in which skeletal muscle is hypertrophied. The results showed that liver mass is comparable and liver:body mass significantly diminished in the null animals compared to age-, sex-, and strain-matched controls. In association with these findings, basal hepatic Akt signaling is decreased, and the expression of the target genes of the constitutive androstane receptor and the integrin-linked kinase are dysregulated in the myostatin-null mice. In addition, the baseline expression levels of the regulators of the G1-S phase cell cycle progression in liver are suppressed in the null mice. The initiation of liver regeneration is not impaired in the null animals, although it progresses toward the lower liver:body mass set point. The data show that skeletal muscle is not the body component against which liver mass is positively regulated, and thus they demonstrate a previously unrecognized systemic compartmental specificity for the regulation of liver:body mass ratio.     

The role of oxidative stress in skeletal muscle injury and regeneration: focus on antioxidant enzymes

Reactive oxygen species (ROS) are generated in skeletal muscle both during the rest and contractile activity. Myogenic cells are equipped with antioxidant enzymes, like superoxide dismutase, catalase, glutathione peroxidase, γ-glutamylcysteine synthetase and heme oxygenase-1. These enzymes not only neutralise excessive ROS, but also affect myogenic regeneration at several stages: influence post-injury inflammatory reaction, enhance viability and proliferation of muscle satellite cells and myoblasts and affect their differentiation. Finally, antioxidant enzymes regulate also processes accompanying muscle regeneration—induce angiogenesis and reduce fibrosis. Elevated ROS production was also observed in Duchenne muscular dystrophy (DMD), a disease characterised by degeneration of muscle tissue and therefore—increased rate of myogenic regeneration. Antioxidant enzymes are consequently considered as target for therapies counteracting dystrophic symptoms. In this review we present current knowledge regarding the role of oxidative stress and systems of enzymatic antioxidant defence in muscular regeneration after both acute injury and persistent muscular degeneration.     

Towards understanding skeletal muscle regeneration

Factors which effect proliferation and fusion of muscle precursor cells have been studied extensively in tissue culture, although little is known about these events in vivo. This review assesses the tissue culture derived data with a view to understanding factors which may control the regeneration of mature skeletal muscle in vivo. The following topics are discussed in the light of recent developments in cell and molecular biology: 1) Injury and necrosis of mature skeletal muscle fibres 2) Phagocytosis of myofibre debris 3) Revascularisation of injured muscle 4) Activation and proliferation of muscle precursor cells (mpc) in vivo Identification of mpcs; Satellite cell relationships; Extracellular matrix; Growth factors; Hormones; Replication. 5) Differentiation and fusion of muscle precursor cells in vivo Differentiation; Fusion; Extracellular matrix; Cell surface molecules: Growth factors and prostaglandins 6) Myotubes and innervation.     

Corticotropin releasing factor 2 receptor agonists reduce the denervation-induced loss of rat skeletal muscle mass and force and increase non-atrophying skeletal muscle mass and force

Of the two corticotropin releasing factor receptors known, corticotrophin releasing factor 2 receptor (CRF2R) is expressed in skeletal muscle. The function of this receptor in skeletal muscle is at present unknown. In order to better understand the role of the CRF2R in skeletal muscle, we treated rats with CRF2R agonists and evaluated the effect of these agents on normal and denervated muscle mass. Rats treated with the non-selective CRFR agonist, sauvagine, did not demonstrate any significant and consistent change in non-denervated and denervated fast twitch [tibialis anterior (TA) or extensor digitorum longus (EDL)] or slow/mixed twitch [medial gastrocnemius (MG) or soleus] fiber muscle mass. In adrenalectomized rats, sauvagine treatment resulted in no significant and consistent change in non-denervated fast or slow/mixed twitch fiber muscles but did cause a significant and consistent increase in denervated fast twitch (TA and EDL) but not slow/mixed twitch muscle mass. Interestingly adrenalectomy had no effect on the degree of muscle atrophy. Rats treated with the CRF2R selective agonist urocortin 2 demonstrated an increase in non-denervated and denervated fast and slow/mix twitch fiber muscle mass. The urocortin 2 induced increase in muscle mass was accompanied by an increase in muscle fiber cross-sectional area and muscle absolute force. These studies demonstrated that activation of the CRF2R decreased the level of skeletal muscle mass, force, and myocyte cross-sectional area loss resulting from sciatic nerve damage and increased the mass, force and myocyte cross-sectional area of normal (non-atrophying) skeletal muscle. In addition, we also observed that removal of the adrenals increased the effectiveness of the non-selective CRFR agonists sauvagine, presumably via the removal of the pro-atrophy influence of adrenal produced corticosteroids. These results demonstrate that pharmacological modulation of the CRF2R may be a viable method to treat skeletal muscle atrophy.     

The regeneration of skeletal muscle in mammals under novocain block

Summary The regenerative process of the skeletal muscles (m, gastrocnemius) was studied in experiments on white mice in conditions of novocain block. It was shown by the histological examination that the course of repair depends on the site of novocain injection. Paranephral novocain block caused a decreased intensity of inflammation and reduction of the reactivity of connective tissue. A parallelism of muscular fibers and their slight dystrophy was noted in these experiments.A significant increase in the intensity of the inflammatory reaction was noted in novocain block of the sympathetic trunk (administration of 0.2 cc of 0.25% novocain solution). The regenerative process varied depending on the character of the novocain injection.Thus, in daily administration of novocain, the prevalence of regeneration of the muscle formations proper was observed, while in injections with 2-day intervals a pre-elective development of connective tissue rich in cells was noted. The structure of the regenerate was different in the mates and in the females.Presented by Active Member AMN SSSR V. N. Chernigovskii     

The regulatory role of melatonin in skeletal muscle

Journal of Muscle Research and Cell Motility - Melatonin (N-acetyl-5-methoxy-tryptamine) is an effective antioxidant and free radical scavenger, that has important biological effects in multiple...     

The role of fibroblasts in self-assembled skeletal muscle

Small facial skeletal muscles often have no autologous donor source to effect surgical reconstruction. Autologously derived muscles could be engineered for replacement tissue, but must be vascularized and innervated to be functional. As a critical step, engineered muscle must mimic the morphology, protein and gene expression, and function of native muscle. This study utilized a self-assembly process to engineer three-dimensional (3D) muscle from a statically strained muscle cell monolayer. Primary mouse myoblasts (PMMs) and mouse embryonic fibroblasts (MEFs) were separately proliferated and coseeded on a fibrin sheet with anchored sutures. Within 10 days of initiating PMM differentiation, the cell-gel layer contracted, lifted, and rolled into a cylindrical 3D structure around the tendon-like suture anchors; the myotubes longitudinally aligned along the lines of tensile force. The objectives of this study were to characterize these engineered muscles and to elucidate the role of the fibroblasts in the self-assembly process. Fibroblasts maintained myotube viability, mediated fibrin degradation, and assisted in muscle self-assembly. The optimal 1:1 PMM:MEF ratio resulted in tissue morphology remarkably similar to native muscle. Through gene and protein expression assays, the development and maturation of the engineered muscle tissue was demonstrated to recapitulate normal skeletal muscle development.     

Bidirectional roles of skeletal muscle fibro-adipogenic progenitors in homeostasis and disease

Sarcopenia and myopathies cause progressive muscle weakness and degeneration, which are closely associated with fat infiltration and fibrosis in muscle. Recently, experimental research has shed light on fibro-adipogenic progenitors (FAPs), also known as muscle-resident mesenchymal progenitors with multiple differentiation potential for adipogenesis, fibrosis, osteogenesis and chondrogenesis. They are considered key regulators of muscle homeostasis and integrity. They play supportive roles in muscle development and repair by orchestrating the regulatory interplay between muscle stem cells (MuSCs) and immune cells. Interestingly, FAPs also contribute to intramuscular fat infiltration, fibrosis and other pathologies when the functional integrity of the network is compromised. In this review, we summarize recent insights into the roles of FAPs in maintenance of skeletal muscle homeostasis, and discuss the underlying mechanisms regulating FAPs behavior and fate, highlighting their roles in participating in efficient muscle repair and fat infiltrated muscle degeneration as well as during muscle atrophy. We suggest that controlling and predicting FAPs differentiation may become a promising strategy to improve muscle function and prevent irreparable muscle damage.     

The role of ribose in human skeletal muscle metabolism

Bioenergetic pathways in muscle provide high-energy compounds that are required for cellular integrity and function. Increased cellular demand for adenosine triphosphate (ATP) or limitations in the rephosphorylation rate of adenosine diphosphate (ADP) can decrease the total adenine nucleotide (TAN) pool, which may take several days to recover or may not recover at all in cases of chronic ischemia. Total adenine nucleotide levels may be significantly decreased as a result of myocardial or skeletal muscle ischemia, certain metabolic diseases, repeated intense skeletal muscle contractions or in repetitive high-intensity exercise. Ribose, a naturally occurring pentose sugar, has been shown to enhance the recovery of myocardial or skeletal muscle ATP and TAN levels following ischemia or high-intensity exercise. Furthermore, ribose has been demonstrated to modulate the production of oxygen free radicals during and following exercise. The following paper reviews skeletal muscle energetics and the potential role of ribose during and following exercise.     

Functional regeneration in the hindlimb skeletal muscle of the mdx mouse

Summary The pattern of spontaneous skeletal muscle degeneration and clinical recovery in hindlimb muscles of the mdx mutant mouse was examined for functional and metabolic confirmation of apparent structural regeneration. The contractile properties, histochemical staining and myosin light chain and parvalbumin contents of extensor digitorum longus (EDL) and soleus (Sol) muscles of mdx and age-matched control mice were studied at 3–4 and 32 weeks. Histochemical staining (myofibrillar ATPase and NADH-tetrazolium reductase) revealed no significant change in slow-twitch-oxidative (SO) or fast-twitch-oxidative-glycolytic (FOG) fibre type proportions in mdx Sol apart from the normal age-related increase in SO fibres. At 32 weeks mdx EDL, however, showed significantly smaller fast-twitch-glycolytic (FG) and larger FOG proportions than those in control EDL. These fibre type distributions were confirmed by differential staining with antibodies to myosin slow-twitch and fast-twitch heavy chain isozymes. Frequency distribution of cross-sectional area for each fibre type showed a wider than normal range of areas especially in FOG fibres of mdx Sol, and FG fibres of mdx EDL, supporting previous observations using autoradiography of myofibre regeneration. Isometric twitch and tetanic tensions in Sol were significantly less than in controls at 4 weeks, but by 32 weeks, values were not different from age-matched controls. In mdx EDL at 3 weeks, twitch and tetanus tensions were significantly less, and time-to-peak twitch tensions were significantly faster than in control EDL. By 32 weeks, mdx EDL twitch and tetanus tensions expressed relative to muscle weight continued to be significantly lower than in age-matched controls, despite normal absolute tensions. The maximum velocity of shortening in 32-week mdx EDL was significantly lower than in control EDL. Myosin light chain distribution in mdx Sol exhibited significantly less light chain 2-slow (LC2s) and more light chain 1b-slow(LC1bs) at 32 weeks than age-matched control Sol. Gels of EDL from 32-week-old mdx mice showed significantly less light chain 2-fast-phosphorylated (LC2f-P) and light chain 3-fast (LC3f) and significantly more light chain 1-fast (LC1f) and light chain 2-fast (LC2f), but normal parvalbumin content compared to age-matched controls. These observations suggest that mdx hindlimb muscles are differentially affected by the disease process as it occurs in murine models of dystrophy. However, the uniqueness of mdx Sol and to a lesser extent EDL is that they also undergo an important degree of functional regeneration which is able to compensate spontaneously for degenerative influences of genetic origin. The mdx mutant may therefore be an important model for the study of regeneration by skeletal muscle, and of the nerve-muscle interactions which enable or restrict that regeneration.     

The role of tropomyosin-troponin in the regulation of skeletal muscle contraction

Summary Steric blocking of actin-myosin interaction by tropomyosin has been a working hypothesis in the study of the regulation of skeletal muscle contraction, yet the simple movement of actin-associated tropomyosin from a myosin-blocking position (relaxation) to a nonblocking position (contraction) cannot adequately account for all of the biophysical and biochemical observations which have been made to date. Ambiguous assignment of tropomyosin positions on actin during contraction, due in part to the limited resolution of reconstruction techniques, may also hint at a real lack of clearcut on and off positioning of tropomyosin and tropomyosin-troponin complex. Recent biochemical evidence suggests processes relatively independent of tropomyosin-troponin may have a governing effect on contraction, involving kinetic constraints on actin-myosin interaction influenced by the binding of ATP and the intermediates of ATP hydrolysis. Based on our current understanding put forth in this review, it is clear that regulatory interactions in muscle contraction do not consist solely of steric effects but involve kinetic factors as well. Where the latter are being defined in systems reconstituted from purified proteins and their fragments, the steric components of regulation are most clearly observed in studies of structurally more intact physiologic systems (e.g. intact or skinned whole muscle fibres). The fine detail of the processes and their interplay remains an intriguing question. Likewise, the precise physical relationship of myosin with actin in the crossbridge cycle continues to elude definition. Refinement of several methodologies (X-ray crystallography, three-dimensional reconstruction, time-resolved X-ray diffraction) will increase the potential for detailing the molecular basis of the regulation of muscle contraction.     

The development of capillaries in post-traumatic regeneration of the skeletal muscle tissue of mammals

Summary The state of islets of Langerhans was investigated in 26 female rats with obesity developed after a bilateral electrolytic lesion of the hypothalamus.In adipose rats an enlargement of the size of islets and of their number occurred at the expense of hypertrophy, hyperplasia, and -cell neoformation. The size of the -cell nucleus was enlarged, this being related to some extent to the degree and duration of the obesity process. In many obese rats degranulation of the -cell cytoplasm was observed, whereas, in some animals, there were degenerative changes in these cells and even complete disintegration of some of them.These data give ground to suppose that in obese rats the functional activity of -cells of the islets is increased, which may lead to their exhaustion as a result of overexertion. This is in accordance with the presence among the obese rats of animals with distinct hyperglycemia and latent diabetes.(Presented by Active Member AMN SSSR V. G. Baranov) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 54, No. 8, pp. 101–104, August, 1962     

Alterations in the calcium homeostasis of skeletal muscle from postmyocardial infarcted rats

In chronic heart failure, skeletal muscles develop a weakness that is not associated to an impaired circulatory function but rather to alterations in the skeletal muscle fibers themselves. To understand these changes, the steps in excitation–contraction coupling of rats that underwent a left anterior coronary artery occlusion were studied. About 24 weeks after the myocardial infarction, neither the total amount nor the voltage dependence of intramembrane charge were altered. In contrast, calcium release from the sarcoplasmic reticulum was considerably suppressed, and its voltage dependence shifted toward more positive voltages. Elementary calcium-release events showed altered morphology as the relative proportion of embers increased. Calcium sparks were smaller in amplitude and had larger time-to-peak values. Isolated ryanodine receptors (RyR) displayed an unusual rectification with increased single-channel conductance at positive (cis vs trans) voltages. In addition, the bell-shaped calcium dependence of channel activity was broader, with a slight shift of activation to lower and a larger shift in inactivation to higher calcium concentrations. These data indicate that the number of channels that open during a calcium-release event is decreased and that RyR function is altered; thus, calcium-release is suppressed after a myocardial infarction. These observations give an explanation for the impaired skeletal muscle function in these animals.