Zeen Gong

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.

Background: The gradual rise in global temperatures can affect skeletal muscle development and intestinal microorganisms. However, the influence of microbial metabolites on skeletal muscle homeostasis under heat stress (HS) remains unclear. Methods: C57BL/6J mice were exposed to normal temperature or 40 °C conditions for 3 d, 7 d, or 14 d. The HS 7 d mice also were treated with sodium butyrate (NaB, 200 mg/kg, gavage). Results: Strikingly, the body weight, antioxidative ability (MDA, T-SOD, and GSH-Px), and average cross-sectional area decreased, but the blood glucose and core temperature increased under HS. However, the NaB treatment reversed these effects. Meanwhile, HS also increased the levels of TNF-α and CORT. Additionally, HS led to a reduction in the villus height and an increase in the crypt depth of the intestine. Microbial 16S rRNA sequencing analysis revealed that HS caused gut microbiota dysbiosis. NaB increased the expression of HSP70 under HS, to maintain skeletal muscle homeostasis. HS stimulated the expression of Pax7, which indicates that skeletal muscle homeostasis was disrupted. Meanwhile, the expressions of MyoG and MyoD were decreased under HS. The immunofluorescence results also show that HS triggered a shift from slow muscle fibers (MYH7) to fast muscle fibers (MYH1). However, NaB recovered the expressions of these muscle-related factors. HS inhibited autophagy initiation (mTOR, Beclin1, Atg5, Atg7, and Atg12), the formation (LC3 II/LC3 I) of autophagosomes, and the binding (p62 and LAMP1) of lysosomes to autophagosomes, which were activated by NaB. C2C12 cells were treated with H₂O₂ to simulate skeletal muscle oxidative stress, and treated with NaB in advance. Oxidative stress disrupted the homeostasis of the C2C12 cells, characterized by an increase in Pax 7 and decreases in MyoG and MyoD, but these changes were reversed by the NaB treatment. Meanwhile, NaB was unable to maintain the stable expression of Pax7 when autophagy was inhibited. Conclusions: This suggests that NaB can regulate oxidative stress induced by HS through autophagy to maintain skeletal muscle homeostasis.

Fluorine is widely present in nature in the form of fluoride. Prolonged high-dose fluoride exposure can cause skeletal fluorosis, resulting in osteosclerosis, osteoporosis or osteomalacia. It has been proved that exercise is one of the important factors affecting the health of the bone and promoting bone formation. To investigate the effects of exercise on bone remodeling in fluorosis mice, 120 male 3-week-old ICR mice were randomly divided into four groups: control group (C), exercise group (E), fluoride group (F), fluoride plus exercise group (F + E). After 8-week physical exercise and/or fluoride exposure, we evaluated the content of fluorine, the histopathological structure and microstructure of femur, bone metabolism biochemical indexes and oxidative stress related parameters, and the mRNA and protein levels of genes in BMP-2/Smads and OPG/RANKL/RANK signaling pathways. Our results showed that 100 mg/L NaF exposure increased the accumulation of fluoride in bone, altered histology of bone, and enhanced the activities of ALP and TRACP. Meanwhile, excessive fluoride induced oxidative stress in bone tissue by increasing the content of ROS and MDA, and decreasing the activities of antioxidant enzymes. In addition, the results of qRT-PCR suggested that NaF significantly increased the mRNA expression of BMP-2, Smad-5, Col IA1, Col IA2, OPG, RANKL and RANK, as well as the elevated proteins of OPG, RANKL and RANK. However, these fluoride-induced changes were alleviated after moderate exercise. Taken together, these findings indicated that moderate exercise decreased the toxicity of fluoride by reducing the accumulation of fluorine in the body to relieve the bone damage caused by fluorosis.