Exerkines in health, resilience and disease

The health benefits of exercise are well-recognized and are observed across multiple organ systems. These beneficial effects enhance overall resilience, healthspan and longevity. The molecular mechanisms that underlie the beneficial effects of exercise, however, remain poorly understood. Since the discovery in 2000 that muscle contraction releases IL-6, the number of exercise-associated signalling molecules that have been identified has multiplied. Exerkines are defined as signalling moieties released in response to acute and/or chronic exercise, which exert their effects through endocrine, paracrine and/or autocrine pathways. A multitude of organs, cells and tissues release these factors, including skeletal muscle (myokines), the heart (cardiokines), liver (hepatokines), white adipose tissue (adipokines), brown adipose tissue (baptokines) and neurons (neurokines). Exerkines have potential roles in improving cardiovascular, metabolic, immune and neurological health. As such, exerkines have potential for the treatment of cardiovascular disease, type 2 diabetes mellitus and obesity, and possibly in the facilitation of healthy ageing. This Review summarizes the importance and current state of exerkine research, prevailing challenges and future directions. Exerkines are signalling moieties that are released in response to acute and/or chronic exercise that exert their effects through endocrine, paracrine and/or autocrine pathways. This Review summarizes the importance and current state of exerkine research, prevailing challenges and future directions. Key points Although the benefits of exercise in enhancing health and treating disease are well-acknowledged, the molecular mechanisms underlying exercise-associated benefits remain ill-defined and are actively being investigated. ‘Exerkines’ encompass a broad variety of signalling moieties released in response to acute and/or chronic exercise that exert their effects through endocrine, paracrine and/or autocrine pathways. Exerkines can come in many forms, such as hormones, metabolites, proteins and nucleic acids; interest is increasing in moving beyond singular changes of specific factors to profiling exerkine alterations using ‘omics’ platforms. There is burgeoning interest in the role of extracellular vesicles, which are membranous structures released from cells, in serving as important carriers of molecular signals and drivers of inter-organ crosstalk related to exercise. Multiple organ systems, including the