Cardiovascular disease is the leading cause of death in the United States. Peripheral arterial disease (PAD) pathology is commonly assumed to be vascular in nature and associated with tissue substrate delivery. Abnormal substrate utilization by skeletal muscle is seldom targeted for investigation, but may contribute equally or greater to disease pathology. The current application addresses the need for critical understanding of the specific roles of endothelial and skeletal muscle cells in the response to cardiovascular disease ischemia/hypoxia. The goal of the Mentored phase of this project is to advance the mechanistic understanding of genetic influence on PAD pathology. Previous and preliminary data support the idea that polymorphisms in the Bcl-2 associated athanogene, BAG3, regulate the response of peripheral limb tissue to ischemic/hypoxic insult. We hypothesize that BAG3 is a critical regulator of the response of both endothelial and skeletal muscle cells to ischemia and that polymorphisms in BAG3 alter its function during this insult. We propose to examine this topic in the following specific aims: 1) determine the role of BAG3 in the specific responses of skeletal muscle and endothelial cells to hypoxic insult, and 2) determine the effect of BAG3 polymorphisms on skeletal muscle and endothelial cell function in response to ischemia/hypoxic insult. This phase of the application will provide training in muscle vascular biology that will facilitate the integration of my muscle biology background into this coordinated research focus. My long-term career goal is to become a successful independent scientist investigating how the dynamic interactions between the vasculature and skeletal myocytes regulate the responses of limb muscle in both physiological and pathophysiological states, including peripheral artery disease, diabetes mellitus, and exercise. My overall hypothesis is that vascular endothelial cells and skeletal muscle interact via biological signaling cascades to propagate cellular survival and or recovery from cachectic insult. I propose to examine this topic in the Independence phase of this award in the following aim: 3) determine novel factors and signaling pathways regulating the interaction of limb muscle vasculature and skeletal myofibers during cardiovascular disease muscle and vascular remodeling. The outcomes of the research proposed in both Mentored and Independent phases will significantly advance the current knowledge of cardiovascular disease associated limb pathology.

Public Health Relevance

Cardiovascular disease is the leading cause of death in the United States. One of the most under-recognized aspects of cardiovascular disease is peripheral arterial disease (PAD). These studies will contribute to the mechanistic understanding of the critical role of genetic influence on PAD pathology, and aid in the development of unique, focused approaches to counteract cardiovascular disease pathology in patient populations.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Transition Award (R00)
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Special Emphasis Panel (NSS)
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Carlson, Drew E
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East Carolina University
Schools of Medicine
United States
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Myers, Valerie D; McClung, Joseph M; Wang, JuFang et al. (2018) The Multifunctional Protein BAG3: A Novel Therapeutic Target in Cardiovascular Disease. JACC Basic Transl Sci 3:122-131
Ryan, Terence E; Yamaguchi, Dean J; Schmidt, Cameron A et al. (2018) Extensive skeletal muscle cell mitochondriopathy distinguishes critical limb ischemia patients from claudicants. JCI Insight 3:
McClung, Joseph M; McCord, Timothy J; Ryan, Terence E et al. (2017) BAG3 (Bcl-2-Associated Athanogene-3) Coding Variant in Mice Determines Susceptibility to Ischemic Limb Muscle Myopathy by Directing Autophagy. Circulation 136:281-296
Schmidt, Cameron A; Ryan, Terence E; Lin, Chien-Te et al. (2017) Diminished force production and mitochondrial respiratory deficits are strain-dependent myopathies of subacute limb ischemia. J Vasc Surg 65:1504-1514.e11
Ryan, Terence E; Schmidt, Cameron A; Alleman, Rick J et al. (2016) Mitochondrial therapy improves limb perfusion and myopathy following hindlimb ischemia. J Mol Cell Cardiol 97:191-6
McClung, Joseph M; McCord, Timothy J; Southerland, Kevin et al. (2016) Subacute limb ischemia induces skeletal muscle injury in genetically susceptible mice independent of vascular density. J Vasc Surg 64:1101-1111.e2
Ryan, Terence E; Schmidt, Cameron A; Green, Thomas D et al. (2016) Targeted Expression of Catalase to Mitochondria Protects Against Ischemic Myopathy in High-Fat Diet-Fed Mice. Diabetes 65:2553-68
Alleman, Rick J; Tsang, Alvin M; Ryan, Terence E et al. (2016) Exercise-induced protection against reperfusion arrhythmia involves stabilization of mitochondrial energetics. Am J Physiol Heart Circ Physiol 310:H1360-70
Padgett, Michael E; McCord, Timothy J; McClung, Joseph M et al. (2016) Methods for Acute and Subacute Murine Hindlimb Ischemia. J Vis Exp :
Mofarrahi, Mahroo; McClung, Joseph M; Kontos, Christopher D et al. (2015) Angiopoietin-1 enhances skeletal muscle regeneration in mice. Am J Physiol Regul Integr Comp Physiol 308:R576-89

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