Molecular bases of the crosstalk between bone and muscle

Abstract

Exercise is an evolutionary conserved survival function that nowadays has beneficial health effects. The increased metabolic activity of contracting skeletal muscle affects the biology of many organs involved in regulating muscle functions. The discovery of hormones and cytokines secreted by bone and skeletal muscle during exercise, has recently added experimental credence to the notion that a crosstalk exists between these organs. Bone through the hormone osteocalcin, promotes exercise capacity in the mouse. After binding to a G-coupled protein receptor, Gprc6a, osteocalcin increases nutrients uptake and catabolism in myofibers during exercise. The catabolic aspect of osteocalcin distinguishes it from insulin signaling. In addition, osteocalcin regulates the endocrine function of skeletal muscle because it enhances the expression of interleukin-6 (IL-6). IL-6 is produced and secreted by contracting skeletal muscle and exerts autocrine, paracrine and systemic effects. One of the systemic functions of IL-6 is to drive the generation of bioactive osteocalcin. Altogether, these studies have revealed a feed-forward loop between bone and skeletal muscle that are necessary and sufficient for optimum exercise capacity. This endocrine regulation of exercise biology, suggest novel and adapted strategies for the prevention or treatment of age related muscle loss.

Keywords: Exercise; IL-6; Osteocalcin.

Fig. 1.

Schematic representation of the physiological functions affected by osteocalcin, lipocalin 2 and FGF23, the three known osteoblast-derived hormones. Osteocalcin stimulates insulin secretion in the pancreas, insulin sensitivity in adipose tissue, nutrients uptake and catabolism inmuscle and testosterone production in the testis. In β-cells, the Leydig cells of the testis and in myofibers, osteocalcin signals through Gprc6a. In addition, osteocalcin promotes monoamine neurotransmitter synthesis and cognitive functions in the brain. FGF23 acts in the kidney to favor phosphate elimination. FGFR1 and Klotho mediate FGF23 signal in the tubular cells of the kidney. Lipocalin 2 binds to the melanocortin 4 receptor in neurons of the hypothalamus to inhibit food intake.

Fig. 2.

Schematic representation of the molecularmechanism of action of osteocalcin in skeletalmuscle during exercise. Circulating levels of undercarboxylated and bioactive osteocalcin increases during exercise. Osteocalcin signals in myofibers through Gprc6a, where it promotes the uptake and catabolism of nutrients. In addition, osteocalcin signaling in myofibers induces the expression of IL-6 and the increase in circulating levels of this myokine. IL-6 signals back to skeletal muscle where it favors glucose and FAs utilization. IL-6 also stimulates FAs production in the white adipose tissue and glucose production in the liver. Furthermore, IL-6 signals to bone to increase the production of bioactive osteocalcin.