Hypoxia: the third wheel between nerve and muscle

Skeletal muscles not only obey carefully all motor commands received via motor nerves from nervous system, but also are ready to modify their structure and function to be more suited to the tasks assigned by nervous system. Thus, nervous system appears as the major modulator of the muscle structure and function. Other factors, however, may interfere with the nerve-muscle partnership and among them, hypoxia plays a pivotal role because skeletal muscles exhibit a great variability of the oxygen fluxes and because hypoxia per se has a powerful influence on muscle fibers. The adaptation of skeletal muscles to nerve-induced activity is particularly evident with low frequency tonic patterns and examples are given by chronic low frequency stimulation and by endurance training. Adaptation includes fiber type transitions towards a slow-oxidative phenotype, increased mitochondrial density and increased capillary/fiber ratio. Hypoxia can trigger some of such changes and this has suggested that low oxygen tension at fiber level might be a mediator, possibly based on HIF and VEGF, of the muscle adaptation to increased contractile activity. Chronic hypoxia can, however, induce opposite modifications, such as a fiber type transition from slow-oxidative to fast-glycolytic and mitochondrial loss. In such conditions, the increased contractile activity can antagonize hypoxia effects. Thus, hypoxia can play a double role in the nerve-muscle relationship, either reinforcing the nerve influence or antagonizing it. This short review aims to re-examine the ambiguous relationships between nerve-induced contractile activity and hypoxic conditions and to suggest possible interpretations of the double role played by hypoxia.