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Muscle and bone are closely associated in both anatomy and function, but the mechanisms that coordinate their synergistic action remain poorly defined. Myostatin, a myokine secreted by muscles, has been shown to inhibit muscle growth, and the disruption of the myostatin gene has been reported to cause muscle hypertrophy and increase bone mass. Extracellular vesicle-exosomes that carry microRNA (miRNA), mRNA, and proteins are known to perform an important role in cell-cell communication. We hypothesized that myostatin may play a crucial role in muscle-bone interactions and may promote direct effects on osteocytes and on osteocyte-derived exosomal miRNAs, thereby indirectly influencing the function of other bone cells. We report herein that myostatin promotes expression of several bone regulators such as sclerostin (SOST), DKK1, and RANKL in cultured osteocytic (Ocy454) cells, concomitant with the suppression of miR-218 in both parent Ocy454 cells and derived exosomes. Exosomes produced by Ocy454 cells that had been pretreated with myostatin could be taken up by osteoblastic MC3T3 cells, resulting in a marked reduction of Runx2, a key regulator of osteoblastic differentiation, and in decreased osteoblastic differentiation via the down-regulation of the Wnt signaling pathway. Importantly, the inhibitory effect of myostatin-modified osteocytic exosomes on osteoblast differentiation is completely reversed by expression of exogenous miR-218, through a mechanism involving miR-218-mediated inhibition of SOST. Together, our findings indicate that myostatin directly influences osteocyte function and thereby inhibits osteoblastic differentiation, at least in part, through the suppression of osteocyte-derived exosomal miR-218, suggesting a novel mechanism in muscle-bone communication.

Spinal cord injury (SCI) results in paralysis and marked loss of skeletal muscle and bone below the level of injury. Modest muscle activity prevents atrophy, whereas much larger--and as yet poorly defined--bone loading seems necessary to prevent bone loss. Once established, bone loss may be irreversible. SCI is associated with reductions in growth hormone, IGF-1, and testosterone, deficiencies likely to exacerbate further loss of muscle and bone. Reduced muscle mass and inactivity are assumed to be contributors to the high prevalence of insulin resistance and diabetes in this population. Alterations in muscle gene expression after SCI share common features with other muscle loss states, but even so, show distinct profiles, possibly reflecting influences of neuromuscular activity due to spasticity. Changes in bone cells and markers after SCI have similarities with other conditions of unloading, although after SCI these changes are much more dramatic, perhaps reflecting the much greater magnitude of unloading. Adiposity and marrow fat are increased after SCI with intriguing, though poorly understood, implications for the function of skeletal muscle and bone cells.

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