P2X receptor signalling in skeletal muscle health and disease

Skeletal muscle (SM) is a heterogeneous and dynamic tissue that changes significantly in its form and function in response to external and internal stimuli and throughout life, from development right through to aging. The fully differentiated SM fiber is a highly specialized, complex and metabolically active cell containing finely tuned assemblies of contractile force-generating proteins, while its growth and repair are maintained by a resident stem cell population. There is increasing evidence that extracellular ATP (ATPe) released during physiological activity and acting on P2 purinoceptors is involved in a number of muscle functions. Furthermore, very high levels of ATPe released from injured muscles can trigger further damage either by altered activation of P2 purinoceptors on muscle cells or by promoting inflammatory cell infiltration. Therefore, the effects of activation of specific P2 purinoceptors in SM can vary from physiologically beneficial to pathologically catastrophic. The most studied in SM so far have been the P2X purinoceptors, which are a family of homo/heterotrimeric ATP-gated ion channels comprised of seven subtypes. Of these P2X1, P2X2, P2X4, P2X5, P2X6, and P2X7 have been identified, so far, predominantly in mouse SM and shown to influence cell growth, differentiation, death, and regeneration in health and disease. There is, however, a considerable diversity in expression of these receptors between different muscle groups and fiber types, which is not fully recognized yet. Understanding the roles of specific P2X purinoceptors in the physiology and pathology of different muscle groups might offer new opportunities for targeted pharmacological intervention in SM diseases.