The Endocrine Actions of Undercarboxylated Osteocalcin in Skeletal Muscle: Effects and Mechanisms

Abstract

Recent evidence has indicated that bone interacts with skeletal muscle, in part, via undercarboxylated osteocalcin (ucOC) - a hormone predominantly secreted from osteoblasts. Experimental studies suggest ucOC has both metabolic and anabolic effects on muscle cells. These effects include improved muscle insulin sensitivity, glucose and fatty acid uptake, mitochondrial function, protein synthesis, as well as myoblast proliferation and differentiation. Current mechanistic evidence also implicates that the underlying mechanisms by which ucOC affects muscle cells include multiple signaling pathways which are orchestrated by its putative receptor - G protein-coupled receptor, class C, group 6, member A (GPRC6A). The ucOC/GPRC6A axis may trigger the activation of signaling cascades involving protein kinase B (Akt), extracellular signal-regulated kinases (ERK), 5' adenosine monophosphate-activated protein kinase (AMPK), and numerous alternative pathways. The identification of the endocrine actions of ucOC in muscle indicates a potential therapeutic avenue for the treatment of muscle insulin resistance and muscle atrophy. However, it is still unknow whether the roles ascribed to ucOC in rodent models translate to humans, as the majority of current studies are performed in cell culture and animal models, while the evidence in humans is relatively scant. Therefore, further research is warranted to clarify similar beneficial effects of ucOC on human skeletal muscle.