Skeletal muscle adaptation to muscle activity and hypoxia: Differential structural and metabolic remodelling

Delivery and utilisation of oxygen are critical determinants of skeletal muscle function, and therefore aerobic performance. Angiogenesis, the process of microvascular bed expansion, may be initiated by several tissue-level stimuli (e.g. of haemodynamic, myogenic or metabolic origin), which are typically present during dynamic exercise. Understanding the relative contribution of these distinct physiological stimuli to skeletal muscle remodelling is needed to develop effective therapeutic strategies to alleviate impaired tissue oxygen supply. In the present study, we uncoupled the predominantly mechanotransductive (i.e. elevated vascular shear stress and cyclical muscle activation) and predominantly chemotransductive (i.e. local tissue hypoxia) stimuli present during exercise by exposing C57b6 mice to either indirect muscle stimulation (10 Hz; ST) or systemic hypoxia (10% oxygen; H), for 7 days, respectively. Furthermore, we combined these stimuli (H+ST) to determine whether the effects were additive. After 7 days of intervention, the tibialis anterior muscle was sampled for histological quantification of microvascular supply and metabolomics analysis. We showed that ST promoted a significant angiogenic response within the muscle whereas H did not. Interestingly, the combined H+ST group had a blunted angiogenic response. Branch-chain amino acid levels were significantly decreased following ST, H and H+ST, consistent with an increased metabolic requirement for ATP, which represents an energy deficit. Proximate metabolites of the glycolytic pathway were significantly reduced following hypoxia, but not stimulation. Together, these observations are commensurate with mechanotransduction triggering structural remodelling of muscle that preserves the metabolome of muscle tissue, whereas chemotransduction inhibits the angiogenic response induced by ST, possibly as a consequence of altered glycolytic metabolism. KEY POINTS: Angiogenesis, the process of microvascular bed expansion, may be initiated by several tissue-level stimuli (e.g. haemodynamic, myogenic or metabolic in origin), which are typically present during dynamic exercise. There has been controversy about the structural (capillary) response of skeletal muscle to altered O₂ status, involving decreased supply (hypoxia) or increased demand (activity). Here, we demonstrate that 7 days of activation of skeletal muscle by indirect electrical stimulation led to significant expansion of the capillary bed. However, a similar adaptive structural response was not observed following hypoxia. When combining indirect stimulation and hypoxia, hypoxia appears to blunt structural remodelling. Proximate metabolites of the glycolytic pathway were significantly reduced following hypoxia, but not stimulation. Together, these observations suggest that mechanotransduction (via indirect stimulation) triggers structural remodelling of muscle that preserves the metabolome of muscle tissue, whereas chemotransduction (via hypoxia) inhibits the angiogenic response induced by stimulation, possibly because of altered glycolytic metabolism.