Carey Fineman Ziter Syndrome (CFZS) is a rare autosomal recessive disease caused by mutations in the MYMK locus which encodes the protein, myomaker. Myomaker is essential for fusion and concurrent myonuclei donation of muscle progenitors during growth and development. Strikingly, in humans, MYMK mutations appear to prompt myofiber hypertrophy but paradoxically, induce generalised muscle weakness. As the underlying cellular mechanisms remain unexplored, the present study aimed to gain insights by combining myofiber deep-phenotyping and proteomic profiling. Hence, we isolated individual muscle fibers from CFZS patients and performed mechanical, 3D morphological and proteomic analyses. Myofibers from CFZS patients were ~ 4x larger than controls and possessed ~ 2x more myonuclei than those from healthy subjects, leading to disproportionally larger myonuclear domain volumes. These greater myonuclear domain sizes were accompanied by smaller intrinsic cellular force generating-capacities in myofibers from CFZS patients than in control muscle cells. Our complementary proteomic analyses indicated remodelling in 233 proteins particularly those associated with cellular respiration. Overall, our findings suggest that myomaker is somewhat functional in CFZS patients, but the associated nuclear accretion may ultimately lead to non-functional hypertrophy and altered energy-related mechanisms in CFZS patients. All of these are likely contributors of the muscle weakness experienced by CFZS patients.

The syncytial mammalian muscle fiber contains a heterogeneous population of (myo)nuclei. At the neuromuscular junction (NMJ), myonuclei have specialized positioning and gene expression. However, it remains unclear how myonuclei are recruited and what regulates myonuclear output at the NMJ. Here, we identify specific properties of myonuclei located near the Drosophila larval NMJ. These synaptic myonuclei have increased size in relation to their surrounding cytoplasmic domain (scaling), increased DNA content (ploidy), and increased levels of transcription factor pMad, a readout for BMP signaling activity. Our genetic manipulations show local BMP signaling affects muscle size, nuclear size, ploidy, and NMJ size and function. In support, RNA sequencing analysis reveals that pMad regulates genes involved in muscle growth, ploidy (i.e., E2f1), and neurotransmission. Our data suggest that muscle BMP signaling instructs synaptic myonuclear output that then positively shapes the NMJ synapse. This study deepens our understanding of how myonuclear heterogeneity supports local signaling demands to fine tune cellular function and NMJ activity.

Proper muscle function and muscle fiber structures that match the environmental demands of organisms are imperative to their success in any ecosystem. The Mexican cavefish, Astyanax mexicanus, has two morphotypes: an obligate cave-dwelling form that lives in thermally insulated caves and an O2 poor environment, and a surface form that lives in a more thermally variable, but O2 rich river environment. As environment can determine physiological adaptations, it is of interest to compare the aerobic and anaerobic metabolic profiles of white muscle metabolism in both morphotypes of this species, as well as their muscle structures. Here, we used white muscle of both morphotypes of the Mexican cavefish to determine citrate synthase (CS) activity as a measure of aerobic potential, and lactate concentration as a measure of anaerobic potential at three different chronic acclimation temperatures (14°C, 25°C, and 31°C). By examining aerobic and anaerobic potential in both morphs, we sought to link environmental thermal flexibility to muscle metabolism. We found that the surface morphotype had higher CS activity and lower lactate concentration, suggesting an overall more efficient usage of aerobic metabolism; whereas the cave morphotype showed lower CS activity and higher lactate concentration, suggesting a stronger reliance on anaerobic pathways. We also measured white muscle histological variables that have been previously linked to whole-animal metabolism: fiber diameter, number of nuclei per mm of fiber and myonuclear domain (MND) of both morphotypes at 25°C to examine cell-level differences in muscle morphology. However, we found no differences in fiber diameter, number of nuclei per mm of fiber or MND between the two morphotypes. Thus, although the cellular morphology is similar in these species, the environmental differences in the evolution of the two morphs has led to differences in their metabolic profiles.

A model explaining the dietary-protein-driven post-natal skeletal muscle growth and protein turnover in the rat is updated, and the mechanisms involved are described, in this narrative review. Dietary protein controls both bone length and muscle growth, which are interrelated through mechanotransduction mechanisms with muscle growth induced both from stretching subsequent to bone length growth and from internal work against gravity. This induces satellite cell activation, myogenesis and remodelling of the extracellular matrix, establishing a growth capacity for myofibre length and cross-sectional area. Protein deposition within this capacity is enabled by adequate dietary protein and other key nutrients. After briefly reviewing the experimental animal origins of the growth model, key concepts and processes important for growth are reviewed. These include the growth in number and size of the myonuclear domain, satellite cell activity during post-natal development and the autocrine/paracrine action of IGF-1. Regulatory and signalling pathways reviewed include developmental mechanotransduction, signalling through the insulin/IGF-1-PI3K-Akt and the Ras-MAPK pathways in the myofibre and during mechanotransduction of satellite cells. Likely pathways activated by maximal-intensity muscle contractions are highlighted and the regulation of the capacity for protein synthesis in terms of ribosome assembly and the translational regulation of 5-TOPmRNA classes by mTORC1 and LARP1 are discussed. Evidence for and potential mechanisms by which volume limitation of muscle growth can occur which would limit protein deposition within the myofibre are reviewed. An understanding of how muscle growth is achieved allows better nutritional management of its growth in health and disease.

It is unclear whether resistance training-induced myofiber hypertrophy is affected by sex, and whether myonuclear addition occurs in relation to the myonuclear domain and can contribute to explaining a potential sex-specific hypertrophic response. This study investigated the effect of 8 wk of resistance training on myofiber hypertrophy and myonuclear addition in 12 males (28 ± 7 yr; mean ± SD) and 12 females (27 ± 7 yr). Muscle biopsies were collected from m. vastus lateralis before and after the training intervention and were analyzed by immunohistochemistry for fiber type and size, satellite cells, and myonuclei. Hypertrophy of type I fibers was greater in males than females (P < 0.05), whereas hypertrophy of type II fibers was similar between sexes (P = 0.158-0.419). Expansion of the satellite cell pool (P = 0.132-0.667) and myonuclear addition (P = 0.064-0.228) did not differ significantly between sexes, irrespective of myofiber type. However, when individual responses to resistance training were assessed, myonuclear addition was strongly correlated with fiber hypertrophy (r = 0.68-0.85, P < 0.001). Although myofiber hypertrophy was accompanied by an increase in myonuclear domain (P < 0.05), fiber perimeter per myonucleus remained constant throughout the study (P = 0.096-0.666). These findings indicate that myonuclear addition occurs in relation to the fiber perimeter per myonucleus, not the myonuclear domain, and has a substantial role in resistance training-induced muscle hypertrophy but does not fully explain greater hypertrophy of type I fibers in males than females.NEW & NOTEWORTHY Here, we show that resistance training-induced hypertrophy of type I fibers is greater in males than females. Myonuclear addition was strongly associated with fiber hypertrophy but did not differ between sexes in type I fibers. Furthermore, whereas muscle hypertrophy was accompanied by an increase in myonuclear domain, fiber perimeter per myonucleus remained constant. Thus, myonuclear addition occurs in relation to fiber perimeter during muscle hypertrophy but does not explain sex-specific hypertrophy of type I fibers.

Phenotypically plastic responses of animals to adjust to environmental variation are pervasive. Reversible plasticity (i.e., phenotypic flexibility), where adult phenotypes can be reversibly altered according to prevailing environmental conditions, allow for better matching of phenotypes to the environment and can generate fitness benefits but may also be associated with costs that trade-off with capacity for flexibility. Here, we review the literature on avian metabolic and muscle plasticity in response to season, temperature, migration and experimental manipulation of flight costs, and employ an integrative approach to explore the phenotypic flexibility of metabolic rates and skeletal muscle in wild birds. Basal (minimum maintenance metabolic rate) and summit (maximum cold-induced metabolic rate) metabolic rates are flexible traits in birds, typically increasing with increasing energy demands. Because skeletal muscles are important for energy use at the organismal level, especially to maximum rates of energy use during exercise or shivering thermogenesis, we consider flexibility of skeletal muscle at the tissue and ultrastructural levels in response to variations in the thermal environment and in workloads due to flight exercise. We also examine two major muscle remodeling regulatory pathways: myostatin and insulin-like growth factor -1 (IGF-1). Changes in myostatin and IGF-1 pathways are sometimes, but not always, regulated in a manner consistent with metabolic rate and muscle mass flexibility in response to changing energy demands in wild birds, but few studies have examined such variation so additional study is needed to fully understand roles for these pathways in regulating metabolic flexibility in birds. Muscle ultrastrutural variation in terms of muscle fiber diameter and associated myonuclear domain (MND) in birds is plastic and highly responsive to thermal variation and increases in workload, however, only a few studies have examined ultrastructural flexibility in avian muscle. Additionally, the relationship between myostatin, IGF-1, and satellite cell (SC) proliferation as it relates to avian muscle flexibility has not been addressed in birds and represents a promising avenue for future study.

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The avian pectoralis muscle demonstrates plasticity with regard to size, so that temperate birds facing winter conditions or birds enduring a migration bout tend to have significant increases in the size and mass of this tissue due to muscular hypertrophy. Myonuclear domain (MND), the volume of cytoplasm a myonuclei services, in the pectoralis muscle of birds seems to be altered during thermal stress or changing seasons. However, there is no information available regarding muscle DNA content or ploidy level within the avian pectoralis. Changes in muscle DNA content can be used in this tissue to aid in size and mass changes. Here, we hypothesized that long-distance migrants or temperate residents would use the process of endoreduplication to aid in altering muscle size. Mostly contradictory to our hypotheses, we found no differences in the mean muscle DNA content in any of the 62 species of birds examined in this study. We also found no correlations between mean muscle DNA content and other muscle structural measurements, such as the number of nuclei per millimeter of fiber, myonuclear domain, and fiber cross-sectional area. Thus, while avian muscle seems more phenotypically plastic than mammalian muscle, the biological processes surrounding myonuclear function may be more closely related to those seen in mammals.

Muscle fibres are multinuclear cells, and the cytoplasmic territory where a single myonucleus controls transcriptional activity is called the myonuclear domain (MND). MND size shows flexibility during muscle hypertrophy. The MND ceiling hypothesis states that hypertrophy results in the expansion of MND size to an upper limit or MND ceiling, beyond which additional myonuclei via activation of satellite cells are required to support further growth. However, the debate about the MND ceiling hypothesis is far from settled, and various studies show conflicting results about the existence or otherwise of MND ceiling in hypertrophy. The aim of this review is to summarise the literature about the MND ceiling in various settings of hypertrophy and discuss the possible factors contributing to a discrepancy in the literature. We conclude by describing the physiological and clinical significance of the MND ceiling limit in the muscle adaptation process in various physiological and pathological conditions.