Sarcopenia (loss of muscle mass and function) universally affects the elderly and has a tremendous impact on quality of life, independent living, and healthcare costs in aging veterans. The goal of this study is to test a potential new pharmacological approach, activation of the sarcoendoplasmic reticulum (SR) calcium ATPase (SERCA) that pumps Ca2+ back into the SR following muscle contraction, to modulate sarcopenia. This work is critically important as no effective pharmacologic interventions currently exist. Here we have employed a mouse model of sarcopenia developed by my laboratory (the Sod1-/- mouse lacking the antioxidant enzyme CuZnSOD) that recapitulates many features of sarcopenia in aging mice and in humans as a pre-clinical model to test and characterize potential interventions. Successful interventions can then be tested further in aging wild type mice. Disrupted intracellular calcium homeostasis is a potential contributor to loss of skeletal muscle mass and force-generating capacity during aging and impaired SERCA function can lead to elevated cytosolic calcium and deleterious effects on cellular processes. We hypothesized that increasing SERCA activity to maintain calcium homeostasis may be an effective mechanism to treat sarcopenia. In support of this, our preliminary data clearly show that treatment of 2 month old Sod1-/- mice with CDN1163, an allosteric SERCA activator, increases SERCA activity, blunts muscle atrophy, improves force generation and reduces muscle mitochondrial ROS production that occurs in the untreated Sod1-/- mice. CDN1163 has reported beneficial effects on metabolism and cognitive function, but our study is the first to test its application as a therapeutic intervention for treating sarcopenia. In this proposal, we will test the hypothesis that SERCA activation can prevent/reduce muscle atrophy and weakness through regulation of cytosolic calcium signaling, mitochondrial function and reduced proteolytic activity. First, we will define dose response and biologic effects of oral administration of CDN1163 in mice through the diet. Once we have determined an optimal effective dose, we will follow up on our exciting data and test whether CDN1163 treatment can prevent/reduce age-related loss of muscle mass and weakness in aging wild type mice in Aim 2. Male and female wildtype C57Bl6 mice will be administered CDN1163 starting at 15 months of age. We will measure the effect of CDN1163 treatment on the regulation of cytosolic calcium signaling, mitochondrial function, contractile function, reduced proteolytic activity and other essential markers of the sarcopenia phenotype at 15, 20, and 28 months of age. SERCA activity is also regulated by an endogenous inhibitor, sarcolipin (Sln). Our studies have shown that sarcolipin is elevated in muscle during aging and in Sod1-/- mice, consistent with reduced SERCA activity.
In Aim 3, we will test whether activation of SERCA through depletion of the SERCA inhibitor sarcolipin modulates sarcopenia in aging Sln-/- mutant mice. We will measure markers of muscle mass, muscle quality, contractile function and metabolic function in response to sarcolipin depletion in 6, 18 and 28 month old male and female wild type and Sln-/- mice. If sarcolipin depletion activates SERCA and modulates muscle atrophy/weakness, this will further support the use of SERCA activators as a therapeutic intervention. Together, these studies have significant potential to reveal a new therapeutic intervention to modulate sarcopenia.
Currently there are no effective pharmacological treatments to reduce age related muscle loss or weakness or the impact of these declines on quality of life in aging veterans because the mechanisms underlying sarcopenia are poorly understood. Here we will determine the effect of targeting improved calcium homeostasis to restore muscle mass and strength in aging. Calcium homeostasis will be targeted through pharmacological restoration of SERCA activity using the compound CDN1163, an allosteric activator of SERCA activity and deletion of the SERCA inhibitor sarcolipin. These findings provide a promising approach towards therapeutic intervention for sarcopenia and a better understanding of the underlying mechanisms.
