Summary Circulating levels of undercarboxylated and bioactive osteocalcin double during aerobic exercise at the time those of insulin decrease. In contrast, circulating levels of osteocalcin plummet early during adulthood in mice, monkeys and humans of both genders. Exploring these observations revealed that osteocalcin signaling in myofibers is necessary for adaptation to exercise by favoring uptake and catabolism of glucose and fatty acids, the main nutrients of myofibers. Osteocalcin signaling in myofibers also accounts for most of the exercise-induced release of interleukin-6, a myokine that promotes adaptation to exercise in part by driving the generation of bioactive osteocalcin. We further show that exogenous osteocalcin is sufficient to enhance the exercise capacity of young mice and to restore to 15 month-old mice the exercise capacity of 3 month-old mice. This study uncovers a bone to muscle feed-forward endocrine axis that favors adaptation to exercise and can reverse the age-induced decline in exercise capacity.

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