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RANK-RANKL signaling in skeletal muscle mitochondrial dynamics

Abstract

The operational unit bone-muscle refers to the mechanical interaction responsible for both bone and muscle muscle and also to the communication via soluble factors that reciprocally regulate bone and muscle metabolism. RANKL (receptor activator of NFkB ligand) and OPG (osteoprotegerin) are examples of osteokynes that together with RANK (receptor activator of NFkB) are essential for osteoclast activation and bone resorption in modeling and remodeling process which requires mitochondrial biogenesis and increase of oxidative capacity of this cell. Many studies show that RANKL is deleterious to muscle fiber in contexts of muscle dystrophy and osteoporosis, however its role in homeostasis and healthy muscle fiber is obscure. Recently, our group has shown that RANK-RANKL signaling induces beige adipocyte differentiation (browning process), which show extensive mitochondrial reticulum and increased energy expenditure. Moreover, treatment with a low dose of RANKL for 28 days elevated the global oxygen consumption in mice, a phenomenon attributed to browning of white subcutaneous adipose tissue. Interestingly, preliminary data showed increased oxygen consumption and SDH (succinyl dehydrogenase) activity in gastrocnemius of RANKL treated mice. Therefore, in the present study, the contribution of RANKL in mitochondrial dynamics and fiber typer switch to oxidative metabolism will be evaluated. The effect of the dose of circulating RANKL will be assessed using OPG-/-, OPG+/- and wild type treated or not with RANKL in aspects of fiber type composition in gastrocnemius and soleus, oxygen consumption, respiratory metabolism and mitochondrial volume. The physiological relevance of these changes will be evaluated during endurance exercise. The molecular mechanisms will be validated in C2C12 cell lineage differentiated to myotubes focusing on mitochondrial biogenesis and dynamics detected by immunofluorescence and RNA-Seq. This study will contribute to expand and provide new insights in the communication between bone-muscle and will clarify the still unreported role of RANKL in the healthy muscle fiber. (AU)

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