Adult Muscle Research Articles

Effect of Body Position on Electrical Activity of Respiratory Muscles During Mouth and Nasal Maximal Respiratory Pressure in Healthy Adults: A Pilot Study

Background: This study aimed to analyze the impact of seated, 45° inclined, and supine positions on respiratory muscle strength (Maximal Inspiratory Pressure—MIP, Maximal Expiratory Pressure—MEP, Sniff Nasal Inspiratory Pressure—SNIP and Sniff Nasal Expiratory Pressure—SNEP) and the electrical activity of respiratory muscles in healthy adults. Ten healthy subjects were evaluated. Methods: Personal, anthropometric data (weight, height, BMI) and lung function (spirometry) were collected, followed by random assessments of inspiratory (MIP, SNIP) and expiratory (MEP, SNEP) muscle strength. Respiratory muscle strength maneuvers and surface electromyographic (sEMG) activity were assessed in sitting, 45° inclined, and supine positions. Results: present that MIP was statistically higher in the sitting position compared to the supine position (p < 0.05) and the 45° supine position (p < 0.05), with SNIP: p < 0.05 and SNEP: p < 0.05 as well. Intercostal muscle activity was higher during MIP, MEP, and SNEP maneuvers in the sitting position (p < 0.05). Additionally, rectus abdominis muscle activity was higher in this position during MIP and SNEP maneuvers. Conclusions: The results suggest there are significant differences in inspiratory pressures between positions, with the difference in activity muscle pattern. In conclusion, body position affected maximal respiratory pressures and influences EMG activation of specific respiratory muscles during MIP.

Cumulative effects of H+ and Pi on force and power of skeletal muscle fibres from young and older adults.

The cellular causes of the age-related loss in power output and increased fatigability are unresolved. We previously observed that the depressive effects of hydrogen (H+) (pH 6.2) and inorganic phosphate (Pi) (30mm) did not differ in muscle fibres from young and older men. However, the effects may have been saturated in the severe fatigue-mimicking condition, potentially masking age differences in the sensitivity of the cross-bridge to these metabolites. Thus, we compared the contractile mechanics of muscle fibres from the vastus lateralis of 13 young (20-32years, seven women) and 12 older adults (70-90years, six women) in conditions mimicking quiescent muscle and a range of elevated H+ (pH 6.8-6.6-6.2) and Pi (12-20-30mm). The older adult knee extensor muscles showed hallmark signs of ageing, including 19% lower thigh lean mass, 60% lower power and a greater fatigability compared to young adult muscles. Progressively increasing concentrations of H+ and Pi in the chemically-permeabilized fibre experiments caused a linear decrease in fibre force, velocity and power; however, the effects did not differ with age or sex. Fast fibre cross-sectional area was 41% smaller in older compared to young adults, which corresponded with lower absolute power. Size-specific power was greater in fibres from older compared to young adults, indicating the age-related decline in absolute power was explained by differences in fibre size. These data suggest the age-related loss in power is determined primarily by fast fibre atrophy in men and women, but the age-related increase in fatigability cannot be explained by an increased sensitivity of the cross-bridge to H+ and Pi. KEY POINTS: The causes of the age-related loss in muscle power output and the increase in fatigability during dynamic exercise remain elusive. We show that progressively increasing concentrations of hydrogen (H+) and inorganic phosphate (Pi) causes a linear decrease in muscle fibre force, velocity and power, but the depressive effects of these metabolites on cross-bridge function did not differ in fibres from older compared to young adults across a range of fatigue-mimicking conditions. We also found peak absolute power did not differ in slow fibres from young and older adults but it was ∼33% lower in older adult fast fibres, which was explained entirely by age differences in fibre size. These data suggest that fast fibre atrophy is a major factor contributing to the loss in power of older men and women, but that the age-related increase in fatigability cannot be explained by an increased sensitivity of the cross-bridge to H+ and Pi.

The strength of associations between ultrasound measures of upper limb muscle morphology and isometric muscle strength: An exploratory study.

Assessing upper limb muscle strength is important for understanding health outcomes, such as daily function and mortality. Ultrasound (US) is increasingly used to evaluate muscle health, but the relationship between its measures of morphology and isometric strength has not been thoroughly explored in upper limb muscles. The aim of this study was to evaluate the associations between US morphological measures and isometric strength in functionally relevant upper limb muscles in healthy adults. Twenty-four healthy volunteers (30.0 ± 10.8 years) underwent B-mode, axial US scans of the first dorsal interosseus (FDI), flexor pollicis longus (FPL), biceps brachii (BB), brachialis (BR), and triceps brachii lateral head (TB). Participants performed corresponding maximal voluntary contractions (MVC), including first digit distal phalanx flexion, second digit abduction, and elbow flexion and extension. US images were segmented to obtain maximal muscle thickness (MT) and cross-sectional area (CSA). Strong positive correlations were found between muscle strength and BB MT (r = .83; p < .001), BR CSA (r = .84; p < .001), and TB MT (r = .70; p < .001). Moderate positive correlations were found for strength and FDI CSA (r = .67; p < .001), FDI MT (r = .47; p < .05), FPL CSA (r = .54; p < .01), and FPL MT (r = .42; p < .05). No significant correlation was found between strength and BR MT (r = .16; p > .05). Our data showed moderate-to-strong associations between US muscle morphology and strength, suggesting that US is likely a good biomarker for strength. However, its use is not "one size fits all." Future investigations should continue to assess this relationship in different muscles and expand the generalizability to clinical populations.

The sodium/ascorbic acid co-transporter SVCT2 distributes in a striated membrane-enriched domain at the M-band level in slow-twitch skeletal muscle fibers

BackgroundVitamin C plays key roles in cellular homeostasis, functioning as a potent antioxidant and a positive regulator of cell differentiation. In skeletal muscle, the vitamin C/sodium co-transporter SVCT2 is preferentially expressed in oxidative slow fibers. SVCT2 is up-regulated during the early fusion of primary myoblasts and decreases during initial myotube growth, indicating the relevance of vitamin C uptake via SVCT2 for early skeletal muscle differentiation and fiber-type definition. However, our understanding of SVCT2 expression and function in adult skeletal muscles is still limited.ResultsIn this study, we demonstrate that SVCT2 exhibits an intracellular distribution in chicken slow skeletal muscles, following a highly organized striated pattern. A similar distribution was observed in human muscle samples, chicken cultured myotubes, and isolated mouse myofibers. Immunohistochemical analyses, combined with biochemical cell fractionation experiments, reveal a strong co-localization of SVCT2 with intracellular detergent-soluble membrane fractions at the central sarcomeric M-band, where it co-solubilizes with sarcoplasmic reticulum proteins. Remarkably, electrical stimulation of cultured myofibers induces the redistribution of SVCT2 into a vesicular pattern.ConclusionsOur results provide novel insights into the dynamic roles of SVCT2 in different intracellular compartments in response to functional demands.

Impaired suppression of fatty acid release by insulin is a strong predictor of reduced whole-body insulin-mediated glucose uptake and skeletal muscle insulin receptor activation.

To examine factors underlying why most, but not all, adults with obesity exhibit impaired insulin-mediated glucose uptake, we compared: (1) adipose tissue fatty acid (FA) release, (2) skeletal muscle lipid droplet (LD) characteristics, and (3) insulin signalling events, in skeletal muscle of adults with obesity with relatively high versus low insulin-mediated glucose uptake. Seventeen adults with obesity (BMI: 36 ± 3 kg/m2) completed a 2 h hyperinsulinemic-euglycemic clamp with stable isotope tracer infusions to measure glucose rate of disappearance (glucose Rd) and FA rate of appearance (FA Ra). Skeletal muscle biopsies were collected at baseline and 30 min into the insulin infusion. Participants were stratified into HIGH (n = 7) and LOW (n = 10) insulin sensitivity cohorts by their glucose Rd during the hyperinsulinemic clamp (LOW< 400; HIGH >550 nmol/kgFFM/min/[μU/mL]). Insulin-mediated suppression of FA Ra was lower in LOW compared with HIGH (p < 0.01). In skeletal muscle, total intramyocellular lipid content did not differ between cohorts. However, the size of LDs in the subsarcolemmal region (SS) of type II muscle fibres was larger in LOW compared with HIGH (p = 0.01). Additionally, insulin receptor-β (IRβ) interactions with regulatory proteins CD36 and Fyn were lower in LOW versus HIGH (p < 0.01), which aligned with attenuated insulin-mediated Tyr phosphorylation of IRβ and downstream insulin-signalling proteins in LOW. Collectively, reduced ability for insulin to suppress FA mobilization, with accompanying modifications in intramyocellular LD size and distribution, and diminished IRβ interaction with key regulatory proteins may be key contributors to impaired insulin-mediated glucose uptake commonly found in adults with obesity.

Clinicopathological collaboration in adult muscle disease: a pragmatic pathway to approach diagnostic dilemmas

Clinicopathological collaboration in adult muscle disease: a pragmatic pathway to approach diagnostic dilemmas

Comparison of Shear-Wave Elastography USG and CT: Composition Analysis of Rectus Femoris Muscle in Healthy Adults and Chronic Kidney Disease Patients.

This study aimed to compare shear-wave elastography (SWE) USG and composition analysis of CT on the right mid-rectus femoris muscle (RF) in both healthy adults and chronic kidney disease (CKD) patients. Sixty-three healthy adults and 22 CKD patients were included. One musculoskeletal radiologist performed right RF SWE USG, while two radiologists measured shear-wave velocity (SWV) from the same SWE images. CT scan was performed, and muscle composition was measured using imageJ, categorized into four HU-based compositions. Interobserver agreement for SWV between two readers was evaluated. Correlations between SWV and CT compositions were analyzed using Pearson's or Spearman's correlation. SWV of healthy group was significantly higher than CKD group by each reader (p = 0.030 and 0.038). The percentage of low-density muscle was higher in CKD group than healthy group (p < 0.001), and the percentage of normal density muscle was higher in healthy group than CKD (p < 0.001) by each reader. Interobserver agreement of SWV by the two readers was almost perfect in both groups (k = 0.957-0.984, 0.959-0.993). There was a statistically significant correlation between SWV and the percentage of normal density muscle on CT in both healthy adults and CKD patient groups (Reader 1, r = 0.318-0.480, p = 0.001 and 0.024; Reader 2, r = 0.511-0.518, p < 0.001 and p = 0.013). SWV demonstrated a significant correlation with the percentage of normal density muscle on CT in both healthy adults and CKD patients by each reader. SWE provides a radiation-free approach that may offer an objective method for evaluating muscle quality, potentially making it an option for muscle monitoring.

Suppressing PDGFRβ Signaling Enhances Myocyte Fusion to Promote Skeletal Muscle Regeneration.

Muscle cell fusion is critical for forming and maintaining multinucleated myotubes during skeletal muscle development and regeneration. However, the molecular mechanisms directing cell-cell fusion are not fully understood. Here, we identify platelet-derived growth factor receptor beta (PDGFRβ) signaling as a key modulator of myocyte fusion in adult muscle cells. Our findings demonstrate that genetic deletion of Pdgfrβ enhances muscle regeneration and increases myofiber size, whereas PDGFRβ activation impairs muscle repair. Inhibition of PDGFRβ activity promotes myonuclear accretion in both mouse and human myotubes, whereas PDGFRβ activation stalls myotube development by preventing cell spreading to limit fusion potential. Transcriptomics analysis show that PDGFRβ signaling cooperates with TGFβ signaling to direct myocyte size and fusion. Mechanistically, PDGFRβ signaling requires STAT1 activation, and blocking STAT1 phosphorylation enhances myofiber repair and size during regeneration. Collectively, PDGFRβ signaling acts as a regenerative checkpoint and represents a potential clinical target to rapidly boost skeletal muscle repair.

An Orai1 gain-of-function tubular aggregate myopathy mouse model phenocopies key features of the human disease.

Tubular aggregate myopathy (TAM) is a heritable myopathy primarily characterized by progressive muscle weakness, elevated levels of creatine kinase (CK), hypocalcemia, exercise intolerance, and the presence of tubular aggregates (TAs). Here, we generated a knock-in mouse model based on a human gain-of-function mutation which results in a severe, early-onset form of TAM, by inducing a glycine-to-serine point mutation in the ORAI1 pore (Orai1G100S/+ or GS mice). By 8 months of age, GS mice exhibited significant muscle weakness, exercise intolerance, elevated CK levels, hypocalcemia, and robust TA presence. Unexpectedly, constitutive Ca2+ entry in mutant mice was observed in muscle only during early development and was abolished in adult skeletal muscle, partly due to reduced ORAI1 expression. Consistent with proteomic results, significant mitochondrial damage and dysfunction was observed in skeletal muscle of GS mice. Thus, GS mice represent a powerful model for investigation of the pathophysiological mechanisms that underlie key TAM symptoms, as well as those compensatory responses that limit the damaging effects of uncontrolled ORAI1-mediated Ca2+ influx.

TMEM16A regulates satellite cell-mediated skeletal muscle regeneration by ensuring a moderate level of caspase 3 activity.

It has been documented that caspase 3 activity is necessary for skeletal muscle regeneration, but how its activity is regulated is largely unknown. Our previous report shows that intracellular TMEM16A, a calcium activated chloride channel, significantly regulates caspase 3 activity in myoblasts during skeletal muscle development. By using a mouse line with satellite cell (SC)-specific deletion of TMEM16A, we examined the role of TMEM16A in regulating caspase 3 activity in SC (or SC-derived myoblast) as well as skeletal muscle regeneration. The mutant animals displayed apparently impaired regeneration capacity in adult muscle along with enhanced ER stress and elevated caspase 3 activity in Tmem16a-/- SC derived myoblasts. Blockade of either excessive ER stress or caspase 3 activity by small molecules significantly restored the inhibited myogenic differentiation of Tmem16a-/- SCs, indicating that excessive caspase 3 activity resulted from TMEM16A deletion contributes to the impaired muscle regeneration and the upstream regulator of caspase 3 was ER stress. Our results revealed an essential role of TMEM16A in satellite cell-mediated skeletal muscle regeneration by ensuring a moderate level of caspase 3 activity.

Overexpression of CPT1A disrupts the maintenance and regenerative function of muscle stem cells.

The skeletal muscle satellite cells (SCs) mediate regeneration of myofibers upon injury. As they switch from maintenance (quiescence) to regeneration, their relative reliance on glucose and fatty acid metabolism alters. To explore the contribution of mitochondrial fatty acid oxidation (FAO) pathway to SCs and myogenesis, we examined the role of carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme of FAO. CPT1A is highly expressed in quiescent SCs (QSCs) compared with activated and proliferating SCs, and its expression level decreases during myogenic differentiation. Myod1Cre-driven overexpression (OE) of Cpt1a in embryonic myoblasts (Cpt1aMTG) reduces muscle weight, grip strength, and contractile force without affecting treadmill endurance of adult mice. Adult Cpt1aMTG mice have reduced number of SC, impairing muscle regeneration and promoting lipid infiltration. Similarly, Pax7CreER-driven, tamoxifen-inducible Cpt1a-OE in QSCs of adult muscles (Cpt1aPTG) leads to depletion of SCs and compromises muscle regeneration. The reduced proliferation of Cpt1a-OE SCs is associated with elevated level of acyl-carnitine, and acyl-carnitine treatment impedes proliferation of wildtype SCs. These findings indicate that aberrant level of CPT1A elevates acyl-carnitine to impair the maintenance, proliferation and regenerative function of SCs.

Functional role of myosin-binding protein H in thick filaments of developing vertebrate fast-twitch skeletal muscle.

Myosin-binding protein H (MyBP-H) is a component of the vertebrate skeletal muscle sarcomere with sequence and domain homology to myosin-binding protein C (MyBP-C). Whereas skeletal muscle isoforms of MyBP-C (fMyBP-C, sMyBP-C) modulate muscle contractility via interactions with actin thin filaments and myosin motors within the muscle sarcomere "C-zone," MyBP-H has no known function. This is in part due to MyBP-H having limited expression in adult fast-twitch muscle and no known involvement in muscle disease. Quantitative proteomics reported here reveal that MyBP-H is highly expressed in prenatal rat fast-twitch muscles and larval zebrafish, suggesting a conserved role in muscle development and prompting studies to define its function. We take advantage of the genetic control of the zebrafish model and a combination of structural, functional, and biophysical techniques to interrogate the role of MyBP-H. Transgenic, FLAG-tagged MyBP-H or fMyBP-C both localize to the C-zones in larval myofibers, whereas genetic depletion of endogenous MyBP-H or fMyBP-C leads to increased accumulation of the other, suggesting competition for C-zone binding sites. Does MyBP-H modulate contractility in the C-zone? Globular domains critical to MyBP-C's modulatory functions are absent from MyBP-H, suggesting that MyBP-H may be functionally silent. However, our results suggest an active role. In vitro motility experiments indicate MyBP-H shares MyBP-C's capacity as a molecular "brake." These results provide new insights and raise questions about the role of the C-zone during muscle development.

Molecular composition of skeletal muscle in infants and adults: a comparative proteomic and transcriptomic study

To gain a deeper understanding of skeletal muscle function in younger age and aging in elderly, identification of molecular signatures regulating these functions under physiological conditions is needed. Although molecular studies of healthy muscle have been conducted on adults and older subjects, there is a lack of research on infant muscle in terms of combined morphological, transcriptomic and proteomic profiles. To address this gap of knowledge, we performed RNA sequencing (RNA-seq), tandem mass spectrometry (LC–MS/MS), morphometric analysis and assays for mitochondrial maintenance in skeletal muscle biopsies from both, infants aged 4–28 months and adults aged 19–65 years. We identified differently expressed genes (DEGs) and differentially expressed proteins (DEPs) in adults compared to infants. The down-regulated genes in adults were associated with functional terms primarily related to sarcomeres, cellular maintenance, and metabolic, immunological and developmental processes. Thus, our study indicates age-related differences in the molecular signatures and associated functions of healthy skeletal muscle. Moreover, the findings assert that processes previously associated solely with aging are indeed part of development and healthy aging. Hence, combined findings of this study also indicate that age-dependent controls are crucial in muscle disease studies, as otherwise the comparative results may not be reliable.

Aging enhances pro-atrogenic gene expression and skeletal muscle loss following respiratory syncytial virus infection.

Aging and many age-related health conditions are associated with skeletal muscle loss. Furthermore, older adults are more susceptible to severe respiratory infections, which can in turn lead to muscle wasting. The mechanisms by which respiratory viral infection can impact skeletal muscle in older adults are not well understood. We determined the effects of acute infection with respiratory syncytial virus (RSV) on the lung and skeletal muscle of aged mice. RSV infection caused more severe disease in aged mice with enhanced weight loss, reduced feeding, higher viral load, and greater airway inflammation. Aged but not young mice showed decreased leg muscle weight at the peak of illness and decreased size of leg muscle fibers. Aged mice increased muscle-specific expression of atrophy-promoting enzymes (Atrogin-1 and MuRF-1) and failed to increase the rate of muscle protein synthesis during RSV infection. In aged mice, the changes in Atrogin-1 and MuRF-1 gene expression in skeletal muscle correlated with IL-6 levels in the lungs. These findings indicate that RSV infection of aged mice provides a model for studying the diverse adverse systemic consequences of respiratory viral infections on health and wellbeing in older adults.

Contribution of vascular endothelium to the regeneration of neuromuscular junctions after degenerative injury to adult skeletal muscle.

Contribution of vascular endothelium to the regeneration of neuromuscular junctions after degenerative injury to adult skeletal muscle.

232VP Patient knowledge of the risks of glucocorticoid management in a specialist adult muscle clinic

232VP Patient knowledge of the risks of glucocorticoid management in a specialist adult muscle clinic

The Innovative Role of Nuclear Receptor Interaction Protein in Orchestrating Invadosome Formation for Myoblast Fusion.

Nuclear receptor interaction protein (NRIP) is versatile and engages with various proteins to execute its diverse biological function. NRIP deficiency was reported to cause small myofibre size in adult muscle regeneration, indicating a crucial role of NRIP in myoblast fusion. The colocalization and interaction of NRIP with actin were investigated by immunofluorescence and immunoprecipitation assay, respectively. The participation of NRIP in myoblast fusion was demonstrated by cell fusion assay and time-lapse microscopy. The NRIP mutants were generated for mechanism study in NRIP-null C2C12 (termed KO19) cells and muscle-specific NRIP knockout (NRIP cKO) mice. A GEO profile database was used to analyse NRIP expression in Duchenne muscular dystrophy (DMD) patients. In this study, we found that NRIP directly and reciprocally interacted with actin both invitro and in cells. Immunofluorescence microscopy showed that the endogenous NRIP colocalized with components of invadosome, such as actin, Tks5, and cortactin, at the tips of cells during C2C12 differentiation. The KO19 cells were generated and exhibited a significant deficit in myoblast fusion compared with wild-type C2C12 cells (3.16% vs. 33.67%, p < 0.005). Overexpressed NRIP in KO19 cells could rescue myotube formation compared with control (3.37% vs. 1.00%, p < 0.01). We further confirmed that NRIP directly participated in cell fusion by using a cell-cell fusion assay. We investigated the mechanism of invadosome formation for myoblast fusion, which depends on NRIP-actin interaction, by analysing NRIP mutants in NRIP-null cells. Loss of actin-binding of NRIP reduced invadosome (enrichment ratio, 1.00 vs. 2.54, p < 0.01) and myotube formation (21.82% vs. 35.71%, p < 0.05) in KO19 cells and forced NRIP expression in KO19 cells and muscle-specific NRIP knockout (NRIP cKO) mice increased myofibre size compared with controls (over 1500 μm2, 61.01% vs. 20.57%, p < 0.001). We also found that the NRIP mRNA level was decreased in DMD patients compared with healthy controls (18 072 vs. 28 289, p < 0.001, N = 10 for both groups). NRIP is a novel actin-binding protein for invadosome formation to induce myoblast fusion.

Differential inclusion of NEB exons 143 and 144 provides insight into NEB-related myopathy variant interpretation and disease manifestation

Biallelic pathogenic variants in the gene encoding nebulin (NEB) are a known cause of congenital myopathy. We present two brothers with congenital myopathy and compound heterozygous variants (NC_000002.12:g.151692086G>T; NM_001271208.2: c.2079C>A; p.(Cys693Ter) and NC_000002.12:g.151533439T>C; NM_001271208.2:c.21522+3A>G ) in NEB. Transcriptomic sequencing on affected individual muscle revealed that the extended splice variant c.21522+3A>G causes exon 144 skipping. Nebulin isoforms containing exon 144 are known to be mutually exclusive with isoforms containing exon 143, and these isoforms are differentially expressed during development and in adult skeletal muscles. Affected individuals MRI patterns of muscle involvement were compared to the known pattern of relative abundance of these two isoforms in muscle. We propose that the pattern of muscle involvement in these affected individuals better fits the distribution of exon 144-containing isoforms in muscle than with previously published MRI findings in NEB-related disease due to other variants. Our report introduces disease pathogenesis and manifestation as a result of alteration of isoform distributions in muscle.

Expression pattern of the fused in sarcoma gene and its contextual influence on the density-specific response of the growth hormone/insulin-like growth factor 1 axis in zig-zag eels (Mastacembelus armatus)

The fused in sarcoma (FUS) protein is a DNA/RNA binding protein from the ten-eleven translocation protein family that is associated with neurodegeneration, and it has been shown to promote cell proliferation through the growth hormone/insulin-like growth factor 1 (Gh/Igf-1) signaling pathway. The zig-zag eel (Mastacembelus armatus) is a newly discovered species exhibiting sexual dimorphism in growth, and the potential role of fus in the growth and development of this species remains largely unknown. Herein, we analyzed the homology, conserved domains, evolutionary characteristics, and conserved syntenies of fus in several teleost species. The expression of fus was predominant in the brain and exhibited sexual dimorphism in the brain, muscle, and liver of zig-zag eels. We found that microRNA (miR)-146-5p, miR-489-3p, and 24 other miRNAs were targeted to the fus 3′ untranslated region, which might affect muscle and bone development in adults. The igf1, insulin-like growth factor 1 receptor a (igf1ra), insulin-like growth factor 2 receptor (igf2r), growth hormone-releasing hormone-like receptor (ghrhrl), growth hormone secretagogue receptor type 1 (ghsr), and glucocorticoid receptor (gr) genes contained a higher abundance of GU-rich fus motifs compared to the other four genes analyzed in zig-zag eels. We also measured the expression of fus mRNA during fish culture at various stocking densities to further elucidate the relationship between fus expression and the Gh/Igf-1 axis. After 100 days of fish cultivation, the expression of fus and ghrhrl decreased and the expression of ghrh and gr increased as the culture density increased (p &amp;lt; 0.05). The expression of fus exhibited a remarkable positive correlation with a specific growth rate. These results indicate that fus mediates growth differences by regulating the expression of several growth-related genes including Gh/Igf-1 axis genes in zig-zag eels.

Skeletal Muscle Satellite Cells Co-Opt the Tenogenic Gene Scleraxis to Instruct Regeneration.

Skeletal muscles connect bones and tendons for locomotion and posture. Understanding the regenerative processes of muscle, bone and tendon is of importance to basic research and clinical applications. Despite their interconnections, distinct transcription factors have been reported to orchestrate each tissue's developmental and regenerative processes. Here we show that Scx expression is not detectable in adult muscle stem cells (also known as satellite cells, SCs) during quiescence. Scx expression begins in activated SCs and continues throughout regenerative myogenesis after injury. By SC-specific Scx gene inactivation (ScxcKO), we show that Scx function is required for SC expansion/renewal and robust new myofiber formation after injury. We combined single-cell RNA-sequencing and CUT&RUN to identify direct Scx target genes during muscle regeneration. These target genes help explain the muscle regeneration defects of ScxcKO, and are not overlapping with Scx -target genes identified in tendon development. Together with a recent finding of a subpopulation of Scx -expressing connective tissue fibroblasts with myogenic potential during early embryogenesis, we propose that regenerative and developmental myogenesis co-opt the Scx gene via different mechanisms.