A circRNA-miRNA-mRNA network potentially regulates skeletal muscle adaptation to hypoxia in Tibetan sheep

The extreme environmental conditions of high-altitude regions, particularly hypoxia, pose significant challenges to animal survival. Tibetan sheep serve as an exemplary model for studying mammalian hypoxic adaptation. Skeletal muscle, crucial for movement and energy metabolism, undergoes adaptive restructuring, yet the underlying molecular mechanisms, particularly the role of the competitive endogenous RNA (ceRNA) network, remain poorly understood. This study aimed to investigate the morphological changes in skeletal muscle across different altitudes and elucidate the potential ceRNA-mediated regulatory mechanisms.

Our results revealed that Tibetan sheep from Qinghai-Tibet Plateau high-altitude (QH) regions exhibited significantly greater muscle fiber diameter and area in the biceps femoris compared to those from lower altitudes. To explore the underlying molecular mechanisms, a circRNA-miRNA-mRNA ceRNA network was constructed, identifying several potential key regulatory axes. These included novel_circ_003862/miR-2440-z/LPL, novel_circ_015124/miR-20-y/LGR4, and novel_circ_012468/miR-2440-z/E2F6. Notably, the expression of LPL and E2F6 was upregulated, while LGR4 was downregulated in the QH group, suggesting a potential coordinated shift towards glycolytic metabolism to maintain energy supply under hypoxic stress.

These findings suggest that hypoxic environments may promote the adaptive remodeling of skeletal muscle fibers by modulating a specific ceRNA network. The altered expression of key genes like LPL, LGR4, and E2F6 potentially enhances glycolytic metabolism to cope with hypoxic stress. This study provides new insights into the molecular genetic basis of high-altitude adaptation in mammals, though experimental validation is required.