Skeletal muscle (SkM) atrophy is a significant health problem associated with muscle disuse. It can frequently occur in association with diseases or treatments of any type that require bed rest or full immobilization. It can result nervous supply injury, or result from chronic diseases, such as cancer, AIDS, diabetes, and importantly, a focus of this proposal, chronic heart failure (HF). Increased physical activity and exercise reduce muscle atrophy or even accelerate its recovery, by causing SkM to undergo metabolic, contractile and morphological adaptations. These adaptations rely on signaling pathways that lead to changes in gene expression and enzymatic activity. Therefore, understanding the molecular mechanisms underlying muscle activity-induced signaling may provide novel basic information about muscle function and adaptation and ultimately could provide new approaches for treating muscle dysfunction, including muscle dysfunction in heart failure. We note that the transcriptional coactivator PGC-1? has been shown to be induced and activated by exercise, and regulate muscle metabolic programs. By using a microarray screen with a myotube model transduced with PGC-1 (PPARgamma coactivator 1) and ERR (Estrogen-related receptor) transcription factors, we identified a novel PGC-1 / ERR target gene, termed Perm1 (PGC-1 and ERR-induced regulator, muscle 1). Our published and preliminary data show that striated muscle protein (Perm1) impacts muscle bioenergetics, is induced by exercise, regulates expression of metabolic genes, and modifies muscle mitochondrial (Mito) biogenesis. Perm1 is also down-regulated in SkM with disuse and the presence of heart failure. Based on this strong preliminary data, we propose the central hypothesis that Perm1 integrates activity-induced signals and enhances muscle mitochondrial biogenesis and function. A corollary to this is that Perm1 acts by modulating activity/contraction?induced kinase signaling (CaMKII, calcium/calmodulin dependent protein kinase II). Through activity-induced signal integration, Perm1 may prevent disuse and HF - induced SkM dysfunction. To address this hypothesis, we have generated two novel mouse models in which Perm1 is either specifically increased in skeletal muscle (Perm1SkMTransgenic (TG)) or deleted from skeletal muscle (Perm1SkM knockout (KO)). This hypothesis will be pursued by the following specific aims:
Aim 1. Study the role of Perm1 in metabolic and functional alterations induced by muscle disuse. We will use Perm1SkMTG and Perm1SkMKO mice to directly evaluate Perm1 function in basal and pathological states including denervation and cast immobilization.
Aim 2. Study the role of Perm1 in Heart Failure-induced SkM dysfunction. We will study the role of Perm1 in HF-induced SkM dysfunction, comparing WT, to Perm1SkMTG, and Perm1SkMKO mice. We hypothesize Perm1SkMTG will be protected from HF-induced SkM weakness and exercise intolerance, while Perm1SkMKO mice will be susceptible to metabolic and functional deregulation induced by HF. Mechanism(s) by which Perm1 effects occur, such as CaMKII-related signaling will be pursued in this aim.
Aim 3. Test the therapeutic benefits of Perm1 for treating SkM dysfunction induced by disuse and heart failure using a gene therapy approach.
This aim will extend to translational work and test how alteration in Perm1 affects muscle function using an adeno-associated virus (AAV) -mediated gene therapy approach to test the therapeutic potential of Perm1 in ameliorating SkM dysfunction. We will test if augmentation of Perm1 expression in SkM will prevent or accelerate recovery from SkM dysfunction. The viruses and models are all in hand. This proposal should uncover important basic and translational information relevant to improve the health of Veterans with skeletal muscle dysfunction present from disuse and importantly, as a result of heart failure.
Loss of skeletal muscle mass or muscle dysfunction is a significant health problem associated with disuse. It can occur in association with diseases or treatments that lead to immobilization, and can also result from chronic diseases, including heart failure. By contrast, exercise is known to reduce muscle atrophy or even accelerate its recovery, by causing skeletal muscle to undergo metabolic and functional adaptations. Understanding the molecular mechanisms underlying these phenomena, may provide novel approaches for treating muscle atrophy, including that which occurs with chronic heart disease. Veterans frequently have illnesses which lead to extended bed rest / immobilization, and as with the entire US population, have a growing number who develop heart failure. Thus, results from this proposal could lead to future new treatments that will impact a large number of VA patients.
