Adiponectin signaling in sarcopenia development and treatment

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The goal of this study is to identify a novel intervention for sarcopenia prevention and treatment. Sarcopenia is the generalized and progressive decline in skeletal muscle mass with age accompanied by either reduced muscle strength or physical performance. Importantly, loss of skeletal muscle mass and function increases the risk for impaired mobility, falls, fractures and mortality and is a major factor in compromised quality of life and loss of independence. Our studies in nonhuman primates have shown that changes in skeletal muscle metabolism and composition anticipate the onset of sarcopenia, shifting the balance of contractile and non- contractile tissue as a result of fiber atrophy, increased intramuscular adiposity, and increased fibrosis. Currently, exercise is the only intervention shown to treat sarcopenia and pharmacological approaches are entirely lacking. Adiponectin is an adipose tissue-derived peptide multimer that impinges on skeletal muscle metabolism to activate lipid utilization and cellular respiratory pathways. Our preliminary data show that the adiponectin receptor agonist AdipoRon activates gene targets involved in the beneficial effects of exercise and enhances contractile force in skeletal muscle from aged mice. We hypothesize that AdipoRon will activate skeletal muscle mitochondria and lipid fuel utilization, resulting in delayed fiber shrinkage, reduced age-associated intramuscular adiposity, and abrogated fibrosis, and that prevention of these age- related changes in muscle composition will directly impinge on physical performance. To test this we will conduct the following studies: In Aim1 translational studies, we will determine the efficacy of adiponectin receptor activation as a means to prevent and treat sarcopenia in mice. Experiments involve AdipoRon treatment in the early and late stages of sarcopenia development and include assessments of muscle composition, physical performance and ex vivo muscle contractile force, and metabolic assessments in gastrocnemius and soleus muscle groups. In Aim2 mechanistic studies, we will determine the impact of AdipoRon on metabolic parameters and cellular mechanisms implicated in skeletal muscle aging. Experiments focus on energy and redox metabolism, lipid metabolism, and inflammation and include novel studies on the mitochondrial acetylome and muscle resident regulatory microRNA. The proposed studies have been informed by our prior work in humans and nonhuman primates and are likely to be highly translatable. These studies are innovative as they introduce a novel therapeutic in the exercise mimetic AdipoRon and include mechanistic and translational components. The identification of novel therapeutic interventions for sarcopenia constitutes a major emphasis in health care today and is clinically relevant to veterans populations where loss of muscle mass and function can arise from disability or injury in addition to aging.