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The variability of fiber type distribution in nine limb muscles was examined with histochemical and tensiomyographical (TMG) methods in two groups of 15 men aged between 17 and 40 years. The aim of this study was to determine the extent to which the relative occurrence of different fiber types and subtypes varies within human limb muscles in function to depth and to predict fiber type proportions with a non-invasive TMG method. The distribution of different fiber types varied within the muscles, as a function of depth, with a predominance of type 2b fibers at the surface and type 1 fibers in deeper regions of the muscle. For all the analyzed muscles the contraction times measured at stimulus intensity 10% of supramaximal stimulus (10% MS) were significantly (p<0.05) shorter than the contraction times measured at 50% of supramaximal stimulus intensity (50% MS). The Pearson's correlation coefficient between percentage of type 1 muscle fibers measured at the surface of the muscle and contraction time at 10% MS, obtained by TMG was statistically significant (r=0.76,P<0.01). Also the Pearson's correlation coefficient between percentage of type 1 muscle fibers measured in the deep region of the muscle and contraction time at 50% MS obtained by TMG was also statistically significant (r=0.90,P<0.001). These findings suggest that the contraction time obtained by TMG may be useful for non-invasive examining of muscle fiber types spatial distribution in humans.

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 muscles include fast and slow muscle fibers. The tibialis anterior muscle (TA) is mainly composed of fast muscle fibers, whereas the soleus muscle (SOL) is mainly composed of slow muscle fibers. However, a noninvasive approach for appropriately investigating the characteristics of muscles is not available. Monitoring of skeletal muscle characteristics can help in the evaluation of the effects of strength training and diseases on skeletal muscles. The present study aimed to determine whether q-space imaging can distinguish between TA and SOL in in vivo mice. In vivo magnetic resonance imaging of the right calves of mice (n = 8) was performed using a 7-Tesla magnetic resonance imaging system with a cryogenic probe. TA and SOL were assessed. q-space imaging was performed with a field of view of 10 mm × 10 mm, matrix of 48 × 48, and section thickness of 1000 μm. There were ten b-values ranging from 0 to 4244 s/mm2, and each b-value had diffusion encoding in three directions. Magnetic resonance imaging findings were compared with immunohistological findings. Full width at half maximum and Kurtosis maps of q-space imaging showed signal intensities consistent with immunohistological findings for both fast (myosin heavy chain II) and slow (myosin heavy chain I) muscle fibers. With regard to quantification, both full width at half maximum and Kurtosis could represent the immunohistological findings that the cell diameter of TA was larger than that of SOL (P < 0.01). q-space imaging could clearly differentiate TA from SOL using differences in cell diameters. This technique is a promising method to noninvasively estimate the fiber type ratio in skeletal muscles, and it can be further developed as an indicator of muscle characteristics.

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.

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 muscle is composed of heterogeneous populations of myofibers that are classified as slow- and fast-twitch fibers. The muscle fiber-type is regulated in a coordinated fashion by multiple genes, including transcriptional factors and microRNAs (miRNAs). However, players involved in this regulation are not fully elucidated. One of the members of the Vestigial-like factors, Vgll2, is thought to play a pivotal role in TEA domain (TEAD) transcription factor-mediated muscle-specific gene expression because of its restricted expression in skeletal muscles of adult mice. Here, we generated Vgll2 null mice and investigated Vgll2 function in adult skeletal muscles. These mice presented an increased number of fast-twitch type IIb fibers and exhibited a down-regulation of slow type I myosin heavy chain (MyHC) gene, Myh7 , which resulted in exercise intolerance. In accordance with the decrease in Myh7 , down-regulation of miR-208b, encoded within Myh7 gene and up-regulation of targets of miR-208b, Sox6, Sp3, and Purβ, were observed in Vgll2 deficient mice. Moreover, we detected the physical interaction between Vgll2 and TEAD1/4 in neonatal skeletal muscles. These results suggest that Vgll2 may be both directly and indirectly involved in the programing of slow muscle fibers through the formation of the Vgll2-TEAD complex.

This investigation examined chronic alteration of the acute hormonal response associated with liquid carbohydrate (CHO) and/or essential amino acid (EAA) ingestion on hormonal and muscular adaptations following resistance training. Thirty-two untrained young men performed 12 weeks of resistance training twice a week, consuming ~675 ml of either, a 6% CHO solution, 6 g EAA mixture, combined CHO + EAA supplement or placebo (PLA). Blood samples were obtained pre- and post-exercise (week 0, 4, 8, and 12), for determination of glucose, insulin, and cortisol. 3-Methylhistidine excretion and muscle fibre cross-sectional area (fCSA) were determined pre- and post-training. Post-exercise cortisol increased (P<0.05) during each training phase for PLA. No change was displayed by EAA; CHO and CHO + EAA demonstrated post-exercise decreases (P<0.05). All groups displayed reduced pre-exercise cortisol at week 12 compared to week 0 (P<0.05). Post-exercise insulin concentrations showed no change for PLA; increases were observed for the treatment groups (P<0.05), which remained greater for CHO and CHO + EAA (P<0.001) than PLA. EAA and CHO ingestion attenuated 3-methylhistidine excretion 48 h following the exercise bout. CHO + EAA resulted in a 26% decrease (P<0.01), while PLA displayed a 52% increase (P<0.01). fCSA increased across groups for type I, IIa, and IIb fibres (P<0.05), with CHO + EAA displaying the greatest gains in fCSA relative to PLA (P<0.05). These data indicate that CHO + EAA ingestion enhances muscle anabolism following resistance training to a greater extent than either CHO or EAA consumed independently. The synergistic effect of CHO + EAA ingestion maximises the anabolic response presumably by attenuating the post-exercise rise in protein degradation.

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 [alpha]-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.

Significance Folliculin interacting protein-1 (Fnip1) is an intracellular protein known to interact with folliculin (a protein mutated in Birt Hogg Dube’ Syndrome) and the master metabolic sensor AMP kinase. However, the roles of Fnip1 in mammalian development and function are unclear. In this study, we used mice deficient in Fnip1 to show that Fnip1 regulates skeletal muscle fiber type specification. Mice deficient in Fnip1 were significantly enriched for highly oxidative skeletal muscle that is more resistant to fatigue than wild-type muscle. Loss of Fnip1 also decreased muscle damage in a mouse model of Duchenne muscular dystrophy. These results reveal a previously unidentified function for Fnip1 and suggest that pharmacological inhibition of Fnip1 may reduce muscle damage in patients with muscular dystrophy. Mammalian skeletal muscle is broadly characterized by the presence of two distinct categories of muscle fibers called type I “red” slow twitch and type II “white” fast twitch, which display marked differences in contraction strength, metabolic strategies, and susceptibility to fatigue. The relative representation of each fiber type can have major influences on susceptibility to obesity, diabetes, and muscular dystrophies. However, the molecular factors controlling fiber type specification remain incompletely defined. In this study, we describe the control of fiber type specification and susceptibility to metabolic disease by folliculin interacting protein-1 (Fnip1). Using Fnip1 null mice, we found that loss of Fnip1 increased the representation of type I fibers characterized by increased myoglobin, slow twitch markers [myosin heavy chain 7 (MyH7), succinate dehydrogenase, troponin I 1, troponin C1, troponin T1], capillary density, and mitochondria number. Cultured Fnip1 -null muscle fibers had higher oxidative capacity, and isolated Fnip1 -null skeletal muscles were more resistant to postcontraction fatigue relative to WT skeletal muscles. Biochemical analyses revealed increased activation of the metabolic sensor AMP kinase (AMPK), and increased expression of the AMPK-target and transcriptional coactivator PGC1α in Fnip1 null skeletal muscle. Genetic disruption of PGC1α rescued normal levels of type I fiber markers MyH7 and myoglobin in Fnip1 -null mice. Remarkably, loss of Fnip1 profoundly mitigated muscle damage in a murine model of Duchenne muscular dystrophy. These results indicate that Fnip1 controls skeletal muscle fiber type specification and warrant further study to determine whether inhibition of Fnip1 has therapeutic potential in muscular dystrophy diseases.

Circulating lipopolysaccharide (LPS) concentrations are often elevated in patients with sepsis or various endogenous diseases related to bacterial translocation from the gut. Systemic inflammatory responses induced by endotoxemia induce severe involuntary loss of skeletal muscle, termed muscle wasting, which adversely affects the survival and functional outcomes of these patients. Currently, no drugs are available for the treatment of endotoxemia-induced skeletal muscle wasting. Here, we tested the effects of TAK-242, a Toll-like receptor 4 (TLR4)-specific signalling inhibitor, on myotube atrophy in vitro and muscle wasting in vivo induced by endotoxin. LPS treatment of murine C2C12 myotubes induced an inflammatory response (increased nuclear factor-κB activity and interleukin-6 and tumour necrosis factor-α expression) and activated the ubiquitin-proteasome and autophagy proteolytic pathways (increased atrogin-1/MAFbx, MuRF1, and LC-II expression), resulting in myotube atrophy. In mice, LPS injection increased the same inflammatory and proteolytic pathways in skeletal muscle and induced atrophy, resulting in reduced grip strength. Notably, pretreatment of cells or mice with TAK-242 reduced or reversed all the detrimental effects of LPS in vitro and in vivo. Collectively, our results indicate that pharmacological inhibition of TLR4 signalling may be a novel therapeutic intervention for endotoxemia-induced muscle wasting.