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Autophagy is essential for the adaptive response to exercise and physiological skeletal muscle functionality. However, the mechanisms leading to the activation of macroautophagy and chaperone-mediated autophagy in human skeletal muscle in response to high-intensity exercise remain elusive. Our findings demonstrate that macroautophagy and chaperone-mediated autophagy are stimulated by high-intensity exercise in normoxia (P I O 2 : 143 mmHg) and severe acute hypoxia (P I O 2 : 73 mmHg) in healthy humans. High-intensity exercise induces macroautophagy initiation through AMPKα phosphorylation, which phosphorylates and activates ULK1. ULK1 phosphorylates BECN1 at Ser 15 , eliciting the dissociation of BECN1-BCL2 crucial for phagophore formation. Besides, high-intensity exercise elevates the LC3B-II:LC3B-I ratio, reduces total SQSTM1/p62 levels, and induces p-Ser 349 SQSTM1/p62 phosphorylation, suggesting heightened autophagosome degradation. PHAF1/MYTHO, a novel macroautophagy biomarker, is highly upregulated in response to high-intensity exercise. The latter is accompanied by elevated LAMP2A expression, indicating chaperone-mediated autophagy activation regardless of post-exercise HSPA8/HSC70 downregulation. Despite increased glycolytic metabolism, severe acute hypoxia does not exacerbate the autophagy signaling response. Signaling changes revert within 1 min of recovery with free circulation, while the application of immediate post-exercise ischemia impedes recovery. Our study concludes that macroautophagy and chaperone-mediated autophagy pathways are strongly activated by high-intensity exercise, regardless of PO 2 , and that oxygenation is necessary to revert these signals to pre-exercise values. PHAF1/MYTHO emerges as a pivotal exercise-responsive autophagy marker positively associated with the LC3B-II:LC3B-I ratio., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Muscle morphological architecture, a crucial determinant of muscle function, has fascinated researchers since the Renaissance. Imaging techniques enable the assessment of parameters such as muscle thickness (MT), pennation angle (PA), and fascicle length (FL), which may vary with growth, sex, and physical activity. Despite known interrelationships, robust mathematical models like causal mediation analysis have not been extensively applied to large population samples. We recruited 109 males and females, measuring knee flexor and extensor, and plantar flexor MT, PA, and FL using real-time ultrasound imaging at rest. A mixed-effects model explored sex, leg (dominant vs. non-dominant), and muscle region differences. Males exhibited greater MT in all muscles (0.1 to 2.1 cm, p < 0.01), with no sex differences in FL. Dominant legs showed greater rectus femoris (RF) MT (0.1 cm, p = 0.01) and PA (1.5°, p = 0.01), while vastus lateralis (VL) had greater FL (1.2 cm, p < 0.001) and PA (0.6°, p = 0.02). Regional differences were observed in VL, RF, and biceps femoris long head (BFlh). Causal mediation analyses highlighted MT's influence on PA, mediated by FL. Moderated mediation occurred in BFlh, with FL differences. Gastrocnemius medialis and lateralis exhibited FL-mediated MT and PA relationships. This study unveils the intricate interplay of MT, FL, and PA in muscle architecture., (© 2024. The Author(s).)

The tibialis anterior muscle plays a critical role in human ambulation and contributes to maintaining the upright posture. However, little is known about its muscle architecture in males and females. One hundred and nine physically active males and females were recruited. Tibialis anterior muscle thickness, pennation angle, and fascicle length were measured at rest in both unipennate regions of both legs using real-time ultrasound imaging. A linear mixed model was used with muscle thickness, pennation angle, or fascicle length as the dependent variables. All models were carried out with and without total leg lean mass and shank length as covariates. Causal mediation analysis was computed to explore the effect of muscle thickness on the relationship between fascicle length and pennation angle. There were no significant differences between dominant and nondominant legs regarding muscle architecture. Muscle thickness and pennation angle were greater in the deep than the superficial unipennate region in males (1.9 mm and 1.1°, p < 0.001) and women (3.4 mm and 2.2°, p < 0.001). However, the fascicle length was similar in both regions for both sexes. The differences remained significant after accounting for differences in leg lean mass and shank length. In both regions, muscle thickness was 1-3 mm greater in males and superficial pennation angle 2° smaller in females (both, p < 0.001). After accounting for leg lean mass and shank length, sex differences remained for muscle thickness (1.6 mm, p < 0.05) and pennation angle (3.4°, p < 0.001) but only in the superficial region. In both regions, leg lean mass and shank-adjusted fascicle length were 1.4 mm longer in females than males (p < 0.05). The causal mediation analysis revealed that the estimation of fascicle length was positive, suggesting that a 10% increase in muscle thickness would augment the fascicle length, allowing a 0.38° pennation angle decrease. Moreover, the pennation angle increases in total by 0.54° due to the suppressive effect of the increase in fascicle length. The estimated mediation, direct, and total effects were all significantly different from zero (p < 0.001). Overall, our results indicate that the architectural anatomy of the tibialis anterior shows sexual dimorphism in humans. Tibialis anterior presents morphological asymmetries between superficial and deep unipennate regions in both sexes. Lastly, our causal mediation model identified a suppressive effect of fascicle length on the pennation angle, suggesting that increments in muscle thickness are not always aligned with increments in fascicle length or the pennation angle., (© 2023 The Authors. Journal of Anatomy published by John Wiley & Sons Ltd on behalf of Anatomical Society.)

The study aimed to determine the levels of skeletal muscle angiotensin-converting enzyme 2 (ACE2, the SARS-CoV-2 receptor) protein expression in men and women and assess whether ACE2 expression in skeletal muscle is associated with cardiorespiratory fitness and adiposity. The level of ACE2 in vastus lateralis muscle biopsies collected in previous studies from 170 men (age: 19-65 years, weight: 56-137 kg, BMI: 23-44) and 69 women (age: 18-55 years, weight: 41-126 kg, BMI: 22-39) was analyzed in duplicate by western blot. VO 2 max was determined by ergospirometry and body composition by DXA. ACE2 protein expression was 1.8-fold higher in women than men (p = 0.001, n = 239). This sex difference disappeared after accounting for the percentage of body fat (fat %), VO 2 max per kg of legs lean mass (VO 2 max-LLM) and age (p = 0.47). Multiple regression analysis showed that the fat % (β = 0.47) is the main predictor of the variability in ACE2 protein expression in skeletal muscle, explaining 5.2% of the variance. VO 2 max-LLM had also predictive value (β = 0.09). There was a significant fat % by VO 2 max-LLM interaction, such that for subjects with low fat %, VO 2 max-LLM was positively associated with ACE2 expression while as fat % increased the slope of the positive association between VO 2 max-LLM and ACE2 was reduced. In conclusion, women express higher amounts of ACE2 in their skeletal muscles than men. This sexual dimorphism is mainly explained by sex differences in fat % and cardiorespiratory fitness. The percentage of body fat is the main predictor of the variability in ACE2 protein expression in human skeletal muscle., (© 2021 The Authors. Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

The signaling pathways activated by Wnt ligands are related to a wide range of critical cell functions, such as cell division, migration, and synaptogenesis. Here, we summarize compelling evidence on the role of Wnt signaling on several features of skeletal muscle physiology. We briefly review the role of Wnt pathways on the formation of muscle fibers during prenatal and postnatal myogenesis, highlighting its role on the activation of stem cells of the adult muscles. We also discuss how Wnt signaling regulates the precise formation of neuromuscular synapses, by modulating the differentiation of presynaptic and postsynaptic components, particularly regarding the clustering of acetylcholine receptors on the muscle membrane. In addition, based on previous evidence showing that Wnt pathways are linked to several diseases, such as Alzheimer's and cancer, we address recent studies indicating that Wnt signaling plays a key role in skeletal muscle fibrosis, a disease characterized by an increase in the extracellular matrix components leading to failure in muscle regeneration, tissue disorganization and loss of muscle activity. In this context, we also discuss the possible cross-talk between the Wnt/β-catenin pathway with two other critical profibrotic pathways, transforming growth factor β and connective tissue growth factor, which are potent stimulators of the accumulation of connective tissue, an effect characteristic of the fibrotic condition. As it has emerged in other pathological conditions, we suggests that muscle fibrosis may be a consequence of alterations of Wnt signaling activity.

The aim of this study was to determine if gender differences in muscle mass explain the gender differences in running and cycling sprint performance. Body composition (dual-energy X-ray absorptiometry), and running (30 and 300 m test) and cycling (Wingate test) sprint performance were assessed in 123 men and 32 women. Peak power (PP) output in the Wingate test expressed per kg of lower extremities lean mass (LM) was similar in males and females (50.4 +/- 5.6 and 50.5 +/- 6.2 W kg(-1), P = 0.88). No gender differences were observed in the slope of the linear relation between LM and PP or mean power output (MP). However, when MP was expressed per kg of LM, the males attained a 22% higher value (26.6 +/- 3.4 and 21.9 +/- 3.2 W kg(-1), P < 0.001). The 30 and 300-m running time divided by the relative lean mass of the lower extremities (RLM = LM x 100/body mass) was significantly lower in males than in females. Although, the slope of the linear relationship between RLM and 300-m running time was not significantly different between genders, the males achieved better performance in the 300-m test than the females. The main factor accounting for gender differences in peak and mean power output during cycling is the muscle mass of the lower extremities. Although, the peak power generating capability of the muscle is similar in males and females, muscle mass only partially explains the gender difference in running sprints, even when expressed as a percentage of the whole body mass.

Heparan sulfate chains of proteoglycans bind to and regulate the function of a wide variety of ligands. In myoblasts, heparan sulfate proteoglycans modulate basic fibroblast growth factor activity and regulate skeletal muscle differentiation. The aim of this study was to identify endogenous extracellular ligands for muscle cell heparan sulfate proteoglycans. [(35)S]heparin ligand blot assays identified a 33/30 kDa doublet (p33/30) in detergent/high ionic strength extracts and heparin soluble fractions obtained from intact C(2)C(12) myoblasts. p33/30 is localized on the plasma membrane or in the extracellular matrix where its level increases during muscle differentiation. Heparin-agarose-purified p33/30 was identified as histone H1. In vitro binding assays showed that histone H1 binds specifically to perlecan. Immunofluorescence microscopy showed that an extracellular pool of histone H1 colocalizes with perlecan in the extracellular matrix of myotube cultures and in regenerating skeletal muscle. Furthermore, histone H1 incorporated into the extracellular matrix strongly stimulated myoblast proliferation via a heparan-sulfate-dependent mechanism. These results indicate that histone H1 is present in the extracellular matrix of skeletal muscle cells, where it interacts specifically with perlecan and exerts a strong proliferative effect on myoblasts, suggesting a role for histone H1 during skeletal muscle regeneration.