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Journal of Applied Physiology... Jan 2024Skeletal muscle is a highly complex tissue that is studied by scientists from a wide spectrum of disciplines, including motor control, biomechanics, exercise science,... (Review)
Review
Skeletal muscle is a highly complex tissue that is studied by scientists from a wide spectrum of disciplines, including motor control, biomechanics, exercise science, physiology, cell biology, genetics, regenerative medicine, orthopedics, and engineering. Although this diversity in perspectives has led to many important discoveries, historically, there has been limited overlap in discussions across fields. This has led to misconceptions and oversimplifications about muscle biology that can create confusion and potentially slow scientific progress across fields. The purpose of this synthesis paper is to bring together research perspectives across multiple muscle fields to identify common assumptions related to muscle fiber type that are points of concern to clarify. These assumptions include ) classification by myosin isoform and fiber oxidative capacity is equivalent, ) fiber cross-sectional area (CSA) is a surrogate marker for myosin isoform or oxidative capacity, and ) muscle force-generating capacity can be inferred from myosin isoform. We address these three fiber-type traps and provide some context for how these misunderstandings can and do impact experimental design, computational modeling, and interpretations of findings, from the perspective of a range of fields. We stress the dangers of generalizing findings about "muscle fiber types" among muscles or across species or sex, and we note the importance for precise use of common terminology across the muscle fields.
Topics: Biomechanical Phenomena; Muscle Fibers, Skeletal; Muscle, Skeletal; Myosins; Protein Isoforms; Biology; Myosin Heavy Chains
PubMed: 37994416
DOI: 10.1152/japplphysiol.00337.2023 -
Aging Cell Oct 2023Sarcopenia is characterized of muscle mass loss and functional decline in elder individuals which severely affects human physical activity, metabolic homeostasis, and...
Sarcopenia is characterized of muscle mass loss and functional decline in elder individuals which severely affects human physical activity, metabolic homeostasis, and life quality. Physical exercise is considered effective in combating muscle atrophy and sarcopenia, yet it is not feasible to elders with limited mobility. PGC-1α4, a short isoform of PGC-1α, is strongly induced in muscle under resistance training, and promotes muscle hypertrophy. In the present study, we showed that the transcriptional levels and nuclear localization of PGC1α4 was reduced during aging, accompanied with muscle dystrophic morphology, and gene programs. We thus designed NLS-PGC1α4 and ectopically express it in myotubes to enhance PGC1α4 levels and maintain its location in nucleus. Indeed, NLS-PGC1α4 overexpression increased muscle sizes in myotubes. In addition, by utilizing AAV-NLS-PGC1α4 delivery into gastrocnemius muscle, we found that it could improve sarcopenia with grip strength, muscle weights, fiber size and molecular phenotypes, and alleviate age-associated adiposity, insulin resistance and hepatic steatosis, accompanied with altered gene signatures. Mechanistically, we demonstrated that NLS-PGC-1α4 improved insulin signaling and enhanced glucose uptake in skeletal muscle. Besides, via RNA-seq analysis, we identified myokines IGF1 and METRNL as potential targets of NLS-PGC-1α4 that possibly mediate the improvement of muscle and adipose tissue functionality and systemic energy metabolism in aged mice. Moreover, we found a negative correlation between PGC1α4 and age in human skeletal muscle. Together, our results revealed that NLS-PGC1α4 overexpression improves muscle physiology and systematic energy homeostasis during aging and suggested it as a potent therapeutic strategy against sarcopenia and aging-associated metabolic diseases.
Topics: Mice; Humans; Animals; Aged; Sarcopenia; Aging; Muscle, Skeletal; Muscle Fibers, Skeletal; Transcription Factors
PubMed: 37584432
DOI: 10.1111/acel.13961 -
Nutrition Journal Jul 2023Resistance training adaptively increases muscle strength and mass, contributing to athletic performance and health promotion. Dietary intervention with natural foods... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Resistance training adaptively increases muscle strength and mass, contributing to athletic performance and health promotion. Dietary intervention with natural foods provides nutrients that help accelerate muscle adaptation to training. Matcha green tea contains several bioactive factors such as antioxidants, amino acids, and dietary fibers; however, its effect on muscle adaptation is unclear. In this study, we aimed to investigate the effects of matcha beverage intake on muscle adaptation to resistance training.
METHODS
Healthy, untrained men were randomized into placebo and matcha groups. Participants consumed either a matcha beverage containing 1.5 g of matcha green tea powder or a placebo beverage twice a day and engaged in resistance training programs for 8 (trial 1) or 12 weeks (trial 2).
RESULTS
In trial 1, maximum leg strength after training tended to increase more in the matcha group than that in the placebo group. In the matcha group, subjective fatigue after exercise at 1 week of training was lower than that in the placebo group. Gut microbe analysis showed that the abundance of five genera changed after matcha intake. The change in Ruminococcus, Butyricimonas, and Oscillospira compositions positively correlated with the change in maximum strength. In trial 2, the change in skeletal muscle mass in response to training was larger in the matcha group. In addition, the salivary cortisol level was lower in the matcha group than that in the placebo group.
CONCLUSION
Daily intake of matcha green tea beverages may help in muscle adaptation to training, with modulations in stress and fatigue responses and microbiota composition.
Topics: Male; Humans; Antioxidants; Resistance Training; Tea; Muscle Strength; Exercise; Muscle, Skeletal
PubMed: 37403052
DOI: 10.1186/s12937-023-00859-4 -
Journal of Cachexia, Sarcopenia and... Oct 2023DJ-1 is a causative gene for Parkinson's disease. DJ-1-deficient mice develop gait-associated progressive behavioural abnormalities and hypoactive forearm grip strength....
BACKGROUND
DJ-1 is a causative gene for Parkinson's disease. DJ-1-deficient mice develop gait-associated progressive behavioural abnormalities and hypoactive forearm grip strength. However, underlying activity mechanisms are not fully explored.
METHODS
Western blotting and quantitative real-time polymerase chain reaction approaches were adopted to analyse DJ-1 expression in skeletal muscle from aged humans or mice and compared with young subjects. Skeletal muscle-specific-DJ-1 knockout (MDKO) mice were generated, followed by an assessment of the physical activity phenotypes (grip strength, maximal load capacity, and hanging, rotarod, and exercise capacity tests) of the MDKO and control mice on the chow diet. Muscular atrophy phenotypes (cross-sectional area and fibre types) were determined by imaging and quantitative real-time polymerase chain reaction. Mitochondrial function and skeletal muscle morphology were evaluated by oxygen consumption rate and electron microscopy, respectively. Tail suspension was applied to address disuse atrophy. RNA-seq analysis was performed to indicate molecular changes in muscles with DJ-1 ablation. Dual-luciferase reporter assays were employed to identify the promoter region of Trim63 and Fbxo32 genes, which were indirectly regulated by DJ-1 via the FoxO1 pathway. Cytoplasmic and nuclear fractions of DJ-1-deleted muscle cells were analysed by western blotting. Compound 23 was administered into the gastrocnemius muscle to mimic the of DJ-1 deletion effects.
RESULTS
DJ-1 expression decreased in atrophied muscles of aged human (young men, n = 2; old with aged men, n = 2; young women, n = 2; old with aged women, n = 2) and immobilization mice (n = 6, P < 0.01). MDKO mice exhibited no body weight difference compared with control mice on the chow diet (Flox, n = 8; MDKO, n = 9). DJ-1-deficient muscles were slightly dystrophic (Flox, n = 7; MDKO, n = 8; P < 0.05), with impaired physical activities and oxidative capacity (n = 8, P < 0.01). In disuse-atrophic conditions, MDKO mice showed smaller cross-sectional area (n = 5, P < 0.01) and more central nuclei than control mice (Flox, n = 7; MDKO, n = 6; P < 0.05), without alteration in muscle fibre types (Flox, n = 6; MDKO, n = 7). Biochemical analysis indicated that reduced mitochondrial function and upregulated of atrogenes induced these changes. Furthermore, RNA-seq analysis revealed enhanced activity of the FoxO1 signalling pathway in DJ-1-ablated muscles, which was responsible for the induction of atrogenes. Finally, compound 23 (an inhibitor of DJ-1) could mimic the effects of DJ-1 ablation in vivo.
CONCLUSIONS
Our results illuminate the crucial of skeletal muscle DJ-1 in the regulation of catabolic signals from mechanical stimulation, providing a therapeutic target for muscle wasting diseases.
Topics: Male; Humans; Animals; Female; Mice; Aged; Muscle, Skeletal; Muscular Atrophy; Muscle Fibers, Skeletal; Muscular Disorders, Atrophic; Mitochondria
PubMed: 37469245
DOI: 10.1002/jcsm.13290 -
Journal of Applied Physiology... Dec 2023Aging is typically associated with decreased muscle strength and rate of force development (RFD), partly explained by motor unit remodeling due to denervation, and...
Aging is typically associated with decreased muscle strength and rate of force development (RFD), partly explained by motor unit remodeling due to denervation, and subsequent loss of fast-twitch type II myofibers. Exercise is commonly advocated to counteract this detrimental loss. However, it is unclear how life-long strength versus endurance training may differentially affect markers of denervation and reinnervation of skeletal myofibers and, in turn, affect the proportion and morphology of fast-twitch type II musculature. Thus, we compared fiber type distribution, fiber type grouping, and the prevalence of atrophic myofibers (≤1,494 µm) in strength-trained (OS) versus endurance-trained (OE) master athletes and compared the results to recreationally active older adults (all >70 yr, OC) and young habitually active references (<30 yr, YC). Immunofluorescent stainings were performed on biopsy samples from vastus lateralis, along with leg press maximal strength and RFD measurements. OS demonstrated similar type II fiber distribution (OS: 52.0 ± 16.4%; YC: 51.1 ± 14.4%), fiber type grouping, maximal strength (OS: 170.0 ± 18.9 kg, YC: 151.0 ± 24.4 kg), and RFD (OS: 3,993 ± 894 N·s, YC: 3,470 ± 1,394 N·s) as young, and absence of atrophic myofibers (OS: 0.2 ± 0.7%; YC: 0.1 ± 0.4%). In contrast, OE and OC exhibited more atrophic fibers (OE: 1.2 ± 1.0%; OC: 1.1 ± 1.4%), more grouped fibers, and smaller proportion of type II fibers (OE: 39.3 ± 11.9%; OC: 35.0 ± 12.4%) than OS and YC (all < 0.05). In conclusion, strength-trained master athletes were characterized by similar muscle morphology as young, which was not the case for recreationally active or endurance-trained old. These results indicate that strength training may preserve type II fibers with advancing age in older men, likely as a result of chronic use of high contractile force generation. Aging is associated with loss of fast-twitch type II myofibers, motor unit remodeling, and grouping of myofibers. This study reveals, for the first time, that strength training preserves neural innervation of type II fibers, resulting in similar myofiber type distribution and grouping in life-long strength-trained master athletes as young moderately active adults. In contrast, life-long endurance-trained master athletes and recreationally active old adults demonstrated higher proportion of type I fibers accompanied by more marked grouping of type I myofibers, and more atrophic fibers compared with strength-trained master athletes and young individuals. Thus, strength training should be utilized as a training modality for preservation of fast-twitch musculature, maximal muscle strength, and rapid force capacity (RFD) with advancing age.
Topics: Male; Humans; Aged; Endurance Training; Muscle Fibers, Skeletal; Aging; Exercise; Muscle Strength; Phenotype; Muscle, Skeletal; Muscle Fibers, Fast-Twitch; Muscle Fibers, Slow-Twitch
PubMed: 37881849
DOI: 10.1152/japplphysiol.00208.2023 -
Nature Communications Jul 2023Skeletal muscle fibers express distinct gene programs during development and maturation, but the underlying gene regulatory networks that confer stage-specific myofiber...
Skeletal muscle fibers express distinct gene programs during development and maturation, but the underlying gene regulatory networks that confer stage-specific myofiber properties remain unknown. To decipher these distinctive gene programs and how they respond to neural activity, we generated a combined multi-omic single-nucleus RNA-seq and ATAC-seq atlas of mouse skeletal muscle development at multiple stages of embryonic, fetal, and postnatal life. We found that Myogenin, Klf5, and Tead4 form a transcriptional complex that synergistically activates the expression of muscle genes in developing myofibers. During myofiber maturation, the transcription factor Maf acts as a transcriptional switch to activate the mature fast muscle gene program. In skeletal muscles of mutant mice lacking voltage-gated L-type Ca channels (Cav1.1), Maf expression and myofiber maturation are impaired. These findings provide a transcriptional atlas of muscle development and reveal genetic links between myofiber formation, maturation, and contraction.
Topics: Mice; Animals; Muscle Fibers, Skeletal; Muscle, Skeletal; Gene Expression Regulation; Transcription Factors; Cell Differentiation
PubMed: 37468485
DOI: 10.1038/s41467-023-40073-8 -
Cells Aug 2023Mitochondria are the primary source of energy production and are implicated in a wide range of biological processes in most eukaryotic cells. Skeletal muscle heavily... (Review)
Review
Mitochondria are the primary source of energy production and are implicated in a wide range of biological processes in most eukaryotic cells. Skeletal muscle heavily relies on mitochondria for energy supplements. In addition to being a powerhouse, mitochondria evoke many functions in skeletal muscle, including regulating calcium and reactive oxygen species levels. A healthy mitochondria population is necessary for the preservation of skeletal muscle homeostasis, while mitochondria dysregulation is linked to numerous myopathies. In this review, we summarize the recent studies on mitochondria function and quality control in skeletal muscle, focusing mainly on in vivo studies of rodents and human subjects. With an emphasis on the interplay between mitochondrial functions concerning the muscle fiber type-specific phenotypes, we also discuss the effect of aging and exercise on the remodeling of skeletal muscle and mitochondria properties.
Topics: Humans; Muscle Fibers, Skeletal; Muscle, Skeletal; Aging; Calcium; Mitochondria
PubMed: 37681915
DOI: 10.3390/cells12172183 -
Science Translational Medicine Oct 2023To date, there are no approved treatments for the diminished strength and paralysis that result from the loss of peripheral nerve function due to trauma, heritable...
To date, there are no approved treatments for the diminished strength and paralysis that result from the loss of peripheral nerve function due to trauma, heritable neuromuscular diseases, or aging. Here, we showed that denervation resulting from transection of the sciatic nerve triggered a marked increase in the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in skeletal muscle in mice, providing evidence that injury drives early expression of this aging-associated enzyme or gerozyme. Treating mice with a small-molecule inhibitor of 15-PGDH promoted regeneration of motor axons and formation of neuromuscular synapses leading to an acceleration in recovery of force after an acute nerve crush injury. In aged mice with chronic denervation of muscles, treatment with the 15-PGDH inhibitor increased motor neuron viability and restored neuromuscular junctions and function. These presynaptic changes synergized with previously reported muscle tissue remodeling to result in a marked increase in the strength of aged muscles. We further found that 15-PGDH aggregates defined the target fibers that are histopathologic hallmarks of human neurogenic myopathies, suggesting that the gerozyme may be involved in their etiology. Our data suggest that inhibition of 15-PGDH may constitute a therapeutic strategy to physiologically boost prostaglandin E2, restore neuromuscular connectivity, and promote recovery of strength after acute or chronic denervation due to injury, disease, or aging.
Topics: Mice; Animals; Humans; Aged; Synapses; Hydroxyprostaglandin Dehydrogenases; Prostaglandins; Muscle, Skeletal; Denervation; Nerve Regeneration
PubMed: 37820010
DOI: 10.1126/scitranslmed.adg1485 -
The Journal of Clinical Investigation Jul 2023Understanding how skeletal muscle fiber proportions are regulated is vital to understanding muscle function. Oxidative and glycolytic skeletal muscle fibers differ in...
Understanding how skeletal muscle fiber proportions are regulated is vital to understanding muscle function. Oxidative and glycolytic skeletal muscle fibers differ in their contractile ability, mitochondrial activity, and metabolic properties. Fiber-type proportions vary in normal physiology and disease states, although the underlying mechanisms are unclear. In human skeletal muscle, we observed that markers of oxidative fibers and mitochondria correlated positively with expression levels of PPARGC1A and CDK4 and negatively with expression levels of CDKN2A, a locus significantly associated with type 2 diabetes. Mice expressing a constitutively active Cdk4 that cannot bind its inhibitor p16INK4a, a product of the CDKN2A locus, were protected from obesity and diabetes. Their muscles exhibited increased oxidative fibers, improved mitochondrial properties, and enhanced glucose uptake. In contrast, loss of Cdk4 or skeletal muscle-specific deletion of Cdk4's target, E2F3, depleted oxidative myofibers, deteriorated mitochondrial function, and reduced exercise capacity, while increasing diabetes susceptibility. E2F3 activated the mitochondrial sensor PPARGC1A in a Cdk4-dependent manner. CDK4, E2F3, and PPARGC1A levels correlated positively with exercise and fitness and negatively with adiposity, insulin resistance, and lipid accumulation in human and rodent muscle. All together, these findings provide mechanistic insight into regulation of skeletal muscle fiber-specification that is of relevance to metabolic and muscular diseases.
Topics: Mice; Animals; Humans; Diabetes Mellitus, Type 2; Muscle Fibers, Skeletal; Muscle Fibers, Slow-Twitch; Muscle, Skeletal; Muscular Diseases; Obesity; Oxidative Stress; Muscle Development; E2F3 Transcription Factor; Cyclin-Dependent Kinase 4
PubMed: 37395281
DOI: 10.1172/JCI162479