The enduring quest for an 'exercise factor': A historical account of skeletal muscle as an endocrine organ

The concept of inter-organ cross-talk, central to understanding physiological adaptations to exercise and disease progression, has been significantly advanced by identifying skeletal muscle as an endocrine organ. This article traces the historical quest for an 'exercise factor', beginning with early speculations in the 19th century and culminating in the discovery of interleukin (IL)-6 as the first myokine and exercise factor in 2003. Initially explored through the works of Julius Geppert and Nathan Zuntz, and later Erling Asmussen and Marius Nielsen, as well as Maurice Goldstein and Bengt Saltin, the search focused on substances released during muscle work, which could influence systemic physiological responses. Despite controversies and the challenge of isolating such factors, the concept gained clarity with the identification of IL-6 that is released from contracting skeletal muscles and plays a crucial role in glucose homeostasis and other processes across various organs, comprising a breakthrough that established skeletal muscle as an endocrine organ.