Cellular and molecular mechanisms of skeletal muscle homeostasis during hibernation

点击翻译按钮获取中文摘要

Skeletal muscle is the largest organ in the human body, comprising ~50% of body mass. Skeletal muscle is necessary to promote several facets of a healthy life, including locomotion, heat production and glucose homeostasis. Loss of skeletal muscle mass can be the result of a variety of conditions including aging, nutrient deprivation and prolonged immobility. This, in turn, increases the incidence of pathologic fractures, functional deterioration, institutionalization and mortality. *Hibernation is an important adaptation strategy among some mammals that allow for survival during prolonged cold temperatures and scarce food supply. Remarkably, although the hibernating animal can be inactive for several months and does not consume food during this time, there is minimal skeletal muscle atrophy. This is in stark contrast to non-hibernating mammals such as mice that can lose almost half of their limb muscle mass after just 12 days of limb immobilization.*The primary objective of the current proposal is to employ an entirely novel and innovative approach to elucidate the cellular and molecular mechanisms involved in preservation of critical skeletal muscle mass and function. We will comprehensively characterize these mechanisms in the 13-lined ground squirrel, an obligate hibernator that enters into a torpid, immobilized state during the winter. As a long-standing model for studies of hibernation, the 13-lined ground squirrel presents a powerful comparative model that may yield valuable insights into fundamental processes of muscle homeostasis.*In order to address the primary objective of our research program, we will organize our studies into four distinct but complimentary projects. Our first project will aim to identify the critical components of two well-defined exercise-induced signaling pathways during protection against atrophy. It has been demonstrated that both pathways are active in the muscle of hibernating ground squirrels simultaneously, in contrast to non-hibernating mammals. In our second project, we will investigate the dependence of muscle protection during hibernation on NAD (nicotinamide adenine dinucleotide), a vital molecule that is required in several enzymatic reactions throughout the cell. Since muscle atrophy has been associated with mitochondrial dysfunction, and NAD is critical to proper mitochondrial function and energy production, we will test the hypothesis that maintaining adequate NAD levels within the mitochondria during hibernation is critical to preserving muscle mass. Our third project will aim to delineate the role of resident skeletal muscle stem cells, known as satellite cells, in the repair process that is initiated by hibernating muscle following injury. These studies will focus on regeneration capacity and fibrosis, since we have previously observed that injured hibernating squirrel muscle regenerates notably slower and lacks fibrosis when compared with active squirrels. Finally, we will test the hypothesis that circulating factors, extrinsic to skeletal muscle, contribute to the maintenance of muscle mass during hibernation by comparing plasma metabolite profiles between active and hibernating ground squirrels. *Together, these projects will provide novel insights and relevant characterization of the mechanisms utilized by hibernating ground squirrels to maintain skeletal muscle mass. They will moreover carry the potential to improve our understanding of the biological mechanisms involved in skeletal muscle preservation and regeneration in non-hibernating mammals.