Wen Sun

Skeletal muscle development and physiological homeostasis are profoundly influenced by environmental cues. Among these factors, ambient temperature represents a critical determinant of growth performance and metabolic adaptation in mammals. However, the effects of different ambient temperature ranges on skeletal muscle characteristics and on responses across multiple visceral tissues remain poorly understood. In this study, five ambient temperature conditions (16 °C, 20 °C, 24 °C, 28 °C, and 32 °C) were established to investigate their physiological impacts in a mouse model. Our results demonstrate that ambient temperature markedly influences growth performance and skeletal muscle phenotype. Notably, mice housed at 20 °C showed relatively preserved grip strength and a shift in myofiber cross-sectional area distribution, although these findings did not consistently indicate superior skeletal muscle development across all indices. Further analysis revealed that ambient temperature significantly modulated the expression profiles of myosin heavy chain (MyHC) isoforms in skeletal muscle. Specifically, cold exposure was associated with an upregulation of the slow-twitch-related MyHC I, whereas heat stress correlated with an elevation of the fast-twitch-related MyHC IIb. Functional assessments indicated that exposure to colder or hotter conditions was associated with impaired muscle performance, as reflected by reduced grip strength at 16 °C, 28 °C, and 32 °C, and decreased endurance capacity at 28 °C and 32 °C. Histological analyses of major visceral organs revealed no obvious structural alterations in the heart, liver, spleen, lung, or kidney across temperature conditions. However, exposure to thermal extremes (16 °C and 32 °C) significantly reduced intestinal villus height, suggesting compromised intestinal integrity under temperature stress. Collectively, these findings indicate that ambient temperature is associated with multi-tissue changes in skeletal muscle characteristics, functional performance, and intestinal morphology. This study provides new insights into how environmental temperature modulates tissue adaptation and physiological homeostasis in mammals.

Sarcopenia, characterized by progressive skeletal muscle mass, strength, and functional loss, imposes a substantial global health burden. Irisin, a myokine derived from fibronectin type III domain-containing protein 5 (FNDC5), is critical for muscle health. Here, we investigate its role in mitigating glucocorticoid-induced sarcopenia using a mouse and C2C12 myotubes model. We quantified FNDC5/irisin levels in skeletal muscle and plasma and assessed muscle function (body weight, grip strength, wire-hanging, and locomotor activity), histology, and mitochondrial features following irisin administration to dexamethasone-treated mice. Western blot analyzed synthesis/hydrolysis regulators, apoptosis markers, and mitochondrial regulators in mouse muscle tissues and C2C12 myotubes. The results show that FNDC5/irisin was significantly downregulated in sarcopenic mice and atrophic C2C12 myotubes; exogenous irisin rescued muscle mass loss and functional impairment, improving body weight, muscle mass, grip strength, and mobility. Mechanistically, irisin bound SIRT1 with −12.7 kcal/mol affinity, activating a deacetylation cascade that suppressed FoxO3a transcriptional activity (attenuating proteasomal degradation) and enhanced mTORC1-mediated protein synthesis in C2C12 myotubes. Additionally, irisin potentiated PGC-1α signaling in mouse myocytes, promoting mitochondrial biogenesis and restoring contractile function in dystrophic fibers. Collectively, these findings demonstrate irisin alleviates glucocorticoid-induced muscle atrophy via SIRT1-dependent pathways, rebalancing muscle physiology and systemic energy homeostasis. This highlights irisin-based therapeutics as a promising exercise surrogate for sarcopenia management, offering novel clinical avenues.

Obesity poses a serious threat to human health, with induced skeletal muscle dysfunction significantly increasing the risk of metabolic syndrome. In obesity, it is known that visceral adipose tissue (VAT) mediates the dysregulation of the adipose–muscle axis through exosome-delivered miRNAs, but the associated regulatory mechanisms remain incompletely elucidated. This study established an AAV-mediated miR-155 obese mouse model and a co-culture system (HFD VAD-evs/RAW264.7 cells/C2C12 cells) to demonstrate that high-fat diet-induced VA-derived extracellular vesicles (HFD VAD-evs) preferentially accumulate in skeletal muscle and induce developmental impairment. HFD VAD-evs disrupt skeletal muscle homeostasis through dual mechanisms: the direct suppression of myoblast development via exosomal miR-155 cargo and the indirect inhibition of myogenesis through macrophage-mediated inflammatory responses in skeletal muscle. Notably, miR-155 inhibition in HFD VAD-evs reversed obesity-associated myogenic deficits. These findings provide novel mechanistic insights into obesity-induced skeletal muscle dysregulation and facilitate potential therapeutic strategies targeting exosomal miRNA signaling.