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Prolonged immobilization of the human body results in functional impairments and musculoskeletal system deconditioning that may be attenuated by adequate muscle exercise. In a 56-day horizontal bed rest campaign involving voluntary males we investigated the effects of vibration muscle exercise (RVE, 2x6 min daily) on the lower limb skeletal muscles using a newly designed foot plantar trainer (Galileo Space) for use at supine position during bed rest. The maximally voluntary isometric plantar flexion force was maintained following regular RVE bouts during bed rest (controls -18.6 %, P<0.05). At the start (BR2) and end of bed rest (BR55) muscle biopsies were taken from both mixed fast/slow-type vastus lateralis (VL) and mainly slow-type soleus muscle (SOL), each having n=10. RVE group: the size of myofiber types I and II was largely unchanged in VL, and increased in SOL. Ctrl group: the SOL depicted a disrupted pattern of myofibers I/II profiles (i.e., type II>140 % vs. preBR) suggesting a slow-to-fast muscle phenotype shift. In RVE-trained SOL, however, an overall conserved myofiber I/II pattern was documented. RVE training increased the activity-dependent expression of nitric oxide synthase type 1 immunofluorescence at SOL and VL myofiber membranes. These data provide evidence for the beneficial effects of RVE training on the deconditioned structure and function of the lower limb skeletal muscle. Daily short RVE should be employed as an effective atrophy countermeasure co-protocol preferentially addressing postural calf muscles during prolonged clinical immobilization or long-term human space missions.

Spinal and bulbar muscular atrophy (SBMA) is a hereditary neuromuscular disorder caused by CAG trinucleotide expansion in the gene encoding the androgen receptor (AR). In the central nervous system, lower motor neurons are selectively affected, whereas pathology of patients and animal models also indicates involvement of skeletal muscle including loss of fast-twitch type 2 fibres and increased slow-twitch type 1 fibres, together with a glycolytic-to-oxidative metabolic switch. Evaluation of muscle and fat using MRI, in addition to biochemical indices such as serum creatinine level, are promising biomarkers to track the disease progression. The serum level of creatinine starts to decrease before the onset of muscle weakness, followed by the emergence of hand tremor, a prodromal sign of the disease. Androgen-dependent nuclear accumulation of the polyglutamine-expanded AR is an essential step in the pathogenesis, providing therapeutic opportunities via hormonal manipulation and gene silencing with antisense oligonucleotides. Animal studies also suggest that hyperactivation of Src, alteration of autophagy and a mitochondrial deficit underlie the neuromuscular degeneration in SBMA and provide alternative therapeutic targets.

Skeletal muscle is a heterogeneous tissue comprised of fibers with different morphological, functional, and metabolic properties. Different muscles contain varying proportions of fiber types; therefore, accurate identification is important. A number of histochemical methods are used to determine muscle fiber type; however, these techniques have several disadvantages. Immunofluorescence analysis is a sensitive method that allows for simultaneous evaluation of multiple MHC isoforms on a large number of fibers on a single cross-section, and offers a more precise means of identifying fiber types. In this investigation we characterized pure and hybrid fiber type distribution in 10 rat and 10 mouse skeletal muscles, as well as human vastus lateralis (VL) using multicolor immunofluorescence analysis. In addition, we determined fiber type-specific cross-sectional area (CSA), succinate dehydrogenase (SDH) activity, and α-glycerophosphate dehydrogenase (GPD) activity. Using this procedure we were able to easily identify pure and hybrid fiber populations in rat, mouse, and human muscle. Hybrid fibers were identified in all species and made up a significant portion of the total population in some rat and mouse muscles. For example, rat mixed gastrocnemius (MG) contained 12.2% hybrid fibers whereas mouse white tibialis anterior (WTA) contained 12.1% hybrid fibers. Collectively, we outline a simple and time-efficient method for determining MHC expression in skeletal muscle of multiple species. In addition, we provide a useful resource of the pure and hybrid fiber type distribution, fiber CSA, and relative fiber type-specific SDH and GPD activity in a number of rat and mouse muscles.

Skeletal muscle conveys several of the health-promoting effects of exercise; yet the underlying mechanisms are not fully elucidated. Studying skeletal muscle is challenging due to its different fiber types and the presence of non-muscle cells. This can be circumvented by isolation of single muscle fibers. Here, we develop a workflow enabling proteomics analysis of pools of isolated muscle fibers from freeze-dried human muscle biopsies. We identify more than 4000 proteins in slow- and fast-twitch muscle fibers. Exercise training alters expression of 237 and 172 proteins in slow- and fast-twitch muscle fibers, respectively. Interestingly, expression levels of secreted proteins and proteins involved in transcription, mitochondrial metabolism, Ca 2+ signaling, and fat and glucose metabolism adapts to training in a fiber type-specific manner. Our data provide a resource to elucidate molecular mechanisms underlying muscle function and health, and our workflow allows fiber type-specific proteomic analyses of snap-frozen non-embedded human muscle biopsies. Skeletal muscle conveys the beneficial effects of physical exercise but due to its heterogeneity, studying the effects of exercise on muscle fibres is challenging. Here, the authors carry out proteomic analysis of myofibres from freeze-dried muscle biopsies, show fibre-type specific changes in response to exercise, and show that the oxidative and glycolytic muscle fibers adapt differentially to exercise training.

Skeletal muscles are classified into slow-twitch muscles composed primarily of type I and IIa fibers with high oxidative metabolism, and fast-twitch muscles composed of type IIx and IIb fibers with high glycolytic metabolism. Fiber-type shifts occur during development and aging; however, the stimuli that shift these types remain unclear. We analyzed the role of mechanical stimuli in myotube formation and shift to the characteristics of each fiber type using crosslinked gelatin gels with tunable elastic moduli (10–230 kPa) and microgrooves (3–50 µm). C2C12 myotubes on 10 kPa gel increased the expression of marker genes for type I and IIa fibers (MYH7 and MYH2 ) and oxidative metabolism ( GLUT4 and myoglobin ) than those on stiffer gels. Upregulation of PGC-1α on soft gel induced a shift toward slow-twitch muscle genetic characteristics. Microgrooves (3–10 µm) enhanced myoblast differentiation and myotube orientation, without affecting the gene expressions characterizing fiber types. This study demonstrated an approach to create highly oriented slow-twitch muscle models by controlling the elasticity and microgrooves.

The composition of skeletal muscle fiber types affects the quality of livestock meat and human athletic performance and health. L-arginine (Arg), a semi-essential amino acid, has been observed to promote the formation of slow-twitch muscle fibers in animal models. However, the precise molecular mechanisms are still unclear. This study investigates the role of Arg in skeletal muscle fiber composition and mitochondrial function through the mTOR signaling pathway. In vivo, 4-week C56BL/6J male mice were divided into three treatment groups and fed a basal diet supplemented with different concentrations of Arg in their drinking water. The trial lasted 7 weeks. The results show that Arg supplementation significantly improved endurance exercise performance, along with increased SDH enzyme activity and upregulated expression of the MyHC I, MyHC IIA, PGC-1α, and NRF1 genes in the gastrocnemius (GAS) and quadriceps (QUA) muscles compared to the control group. In addition, Arg activated the mTOR signaling pathway in the skeletal muscle of mice. In vitro experiments using cultured C2C12 myotubes demonstrated that Arg elevated the expression of slow-fiber genes (MyHC I and Tnnt1) as well as mitochondrial genes (PGC-1α, TFAM, MEF2C, and NRF1), whereas the effects of Arg were inhibited by the mTOR inhibitor rapamycin. In conclusion, these findings suggest that Arg modulates skeletal muscle fiber type towards slow-twitch fibers and enhances mitochondrial functions by upregulating gene expression through the mTOR signaling pathway.

Skeletal muscle is a highly heterogeneous tissue, and its contractile proteins are composed of different isoforms, forming various types of muscle fiber, each of which has its own metabolic characteristics. It has been demonstrated that endurance exercise induces the transition of muscle fibers from fast-twitch to slow-twitch muscle fiber type. Herein, we discover a novel epigenetic mechanism for muscle contractile property tightly coupled to its metabolic capacity during muscle fiber type transition with exercise training. Our results show that an 8-week endurance exercise induces histone methylation remodeling of PGC-1α and myosin heavy chain (MHC) isoforms in the rat gastrocnemius muscle, accompanied by increased mitochondrial biogenesis and an elevated ratio of slow-twitch to fast-twitch fibers. Furthermore, to verify the roles of reactive oxygen species (ROS) and AMPK in exercise-regulated epigenetic modifications and muscle fiber type transitions, mouse C2C12 myotubes were used. It was shown that rotenone activates ROS/AMPK pathway and histone methylation enzymes, which then promote mitochondrial biogenesis and MHC slow isoform expression. Mitoquinone (MitoQ) partially blocking rotenone-treated model confirms the role of ROS in coupling mitochondrial biogenesis with muscle fiber type. In conclusion, endurance exercise couples mitochondrial biogenesis with MHC slow isoform by remodeling histone methylation, which in turn promotes the transition of fast-twitch to slow-twitch muscle fibers. The ROS/AMPK pathway may be involved in the regulation of histone methylation enzymes by endurance exercise.

Skeletal muscle expresses three types of non-muscle myosin (NM) II in addition to skeletal type myosin. While immature myoblasts have been reported to express NMIIA and NMIIB, playing roles in cell morphology, the specific localization and function of NMIIC in skeletal muscle cells remain unclear. In this study, we aimed to investigate the expression pattern and the physiological role of NMIIC in skeletal muscle. NMIIC was specifically expressed in the slow-twitch muscles such as soleus, which primarily consists of type I and type IIa fibers, and its expression increased as muscle differentiation progressed. To explore the function of NMIIC in skeletal muscle, we used whole-body NMIIC knockout (KO) mice. Myofiber size was slightly but significantly decreased in the soleus of young (18-20-week-old) NMIIC KO mice. However, contractile force of the isolated soleus muscle in the NMIIC KO mice did not differ from that of wild-type mice, suggesting that the slight reduction in fiber size has limited physiological significance at this age. Interestingly, in 81-week-old NMIIC KO mice, soleus contractile force was significantly reduced despite no difference in fiber size between aged wild-type and NMIIC KO mice. Notably, NMIIC expression levels were higher in aged than young mice. These findings suggest that while NMIIC has minimal impact on skeletal muscle function under young and healthy conditions, it may play a crucial role in maintaining muscle function when muscle is compromised at age.

Sarcopenia is distinct from normal muscle atrophy in that it is closely related to a shift in the muscle fiber type. Deficiency of the anabolic action of androgen on skeletal muscles is associated with sarcopenia; however, the function of the androgen receptor (AR) pathway in sarcopenia remains poorly understood. We generated a mouse model (fast-twitch muscle-specific AR knockout [fmARKO] mice) in which the AR was selectively deleted in the fast-twitch muscle fibers. In young male mice, the deletion caused no change in muscle mass, but it reduced muscle strength and fatigue resistance and induced a shift in the soleus muscles from fast-twitch fibers to slow-twitch fibers (14% increase, P = 0.02). After middle age, with the control mice, the male fmARKO mice showed much less muscle function, accompanied by lower hindlimb muscle mass; this phenotype was similar to the progression of sarcopenia. The bone mineral density of the femur was significantly reduced in the fmARKO mice, indicating possible osteosarcopenia. Microarray and gene ontology analyses revealed that in male fmARKO mice, there was downregulation of polyamine biosynthesis-related geneswhich was confirmed by liquid chromatography–tandem mass spectrometry assay and the primary cultured myofibers. None of the AR deletion-related phenotypes were observed in female fmARKO mice. Our findings showed that the AR pathway had essential muscle type- and sex-specific roles in the differentiation toward fast-twitch fibers and in the maintenance of muscle composition and function. The AR in fast-twitch muscles was the dominant regulator of muscle fiber-type composition and muscle function, including the muscle–bone relationship.

The global prevalence of skeletal muscle diseases has progressively escalated in recent years. This study aimed to explore the potential role of matrix stiffness in the repair mechanisms following skeletal muscle injury. We observed an increase in muscle stiffness, a significant rise in the number of type I muscle fibres and a notable elevation in mRNA expression levels of Myh7/2 alongside a decrease in Myh1/4 on day 3 post tibialis anterior muscle injury. To replicate these in vivo changes, C2C12 cells were cultured under high matrix stiffness conditions, and compared to those on low matrix stiffness, the C2C12 cells cultured on high matrix stiffness showed increased expression levels of Myh7/2 mRNA and production levels of MYH7/2, indicating differentiation into slow‐twitch muscle fibre types. Furthermore, up‐regulation of DRP1 phosphorylation along with elevated F‐actin fluorescence intensity and RHOA and ROCK1 production indicates that high matrix stiffness induces cytoskeletal remodelling to regulate mitochondrial fission processes. Our data also revealed up‐regulation in mRNA expression level for Actb, phosphorylation level for DRP1, mitochondrial quantity and MYH7/2 production level. Importantly, these effects were effectively reversed by the application of ROCK inhibitor Y‐27632, highlighting that targeting cytoskeletal dynamics can modulate myogenic differentiation pathways within C2C12 cells. These findings provide valuable insights into how matrix stiffness influences fibre type transformation during skeletal muscle injury repair while suggesting potential therapeutic targets for intervention.