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Principal Investigator: Barchowsky, Aaron
Institute Receiving Award University Of Pittsburgh At Pittsburgh
Location Pittsburgh, PA
Grant Number R01ES033519
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 23 Jul 2021 to 30 Apr 2026
DESCRIPTION (provided by applicant): PROJECT DESCRIPTION / ABSTRACT Declines in muscle quality and impaired metabolism are major contributing factors to cardiovascular disease morbidity and mortality. Loss of lean body mass and muscle vitality not only impairs mobility, but also contributes to worsening of a large range of systemic disease outcomes. Environmental exposure to arsenic is strongly associated with cardiovascular and metabolic disease in millions of individuals globally. However, the underlying pathogenic mechanisms for these increased risks are relatively unknown. The proposed studies seek to fill this knowledge gap by investigating the hypothesis that arsenic impairs muscle progenitor cell function and differentiation to promote declines in muscle quality and composition, as well as disrupt communication of healthy muscle metabolism with systemic organs. We find that low to moderate environmental exposure to arsenic in drinking water promotes skeletal muscle decline by disrupting muscle composition and structure, as well as injuring mitochondria and altering mitochondrial bioenergetics. In addition, we find fibroadipogenic remodeling of the muscle that resembles myosteatosis, a major risk factor for cardiovascular mortality and type 2 diabetes in humans. Mechanistically, stem cell mitochondria targeted by arsenic promote epigenetic induction of pathogenic progenitor cell phenotypes and differentiation. It is important to resolve the mechanisms for dysfunctional mitochondrial and nuclear epigenetic communication in order to identify strategies that restore normal muscle metabolism. Towards this goal, the studies in specific Aim 1 will test the hypothesis that dysfunctional mitochondrial communication drives pathogenic metabolic and phenotypic changes in progenitor cells and their niche that dictate muscle maintenance and adiposity. Importantly, we will use a mitochondrial protective peptide to determine whether reversing the mitochondrial effects of arsenic restores normal epigenetic regulation, stem cell phenotypes, and muscle metabolism. The goal of the studies in specific Aim 2 is to test the hypothesis that maladaptive mitochondrial phenotypes drive pathogenic paracrine and systemic communication. These studies focus on dysfunctional paracrine and systemic signaling mediated by miRNA cargo in extracellular vesicles released from arsenic- exposed muscle progenitor cells and skeletal muscles. We will identify the effects of arsenic on the profile of miRNA cargo and determine whether this altered profile affects metabolism in systemic organs, such as the liver. As in Aim 1, we will intervene with mitochondrial protective agents to determine whether the miRNA cargo profiles and organ metabolism can be restored to normal. If successful, these studies will identify clinically-relevant and immediately-tractable strategies to reverse pathogenic muscle maintenance and loss of regenerative capacity from chronic arsenic exposures. The greater impact will be the identification of strategies to reduce the contribution of arsenic to the global burden of metabolic and cardiovascular diseases, an ever-increasing concern in aging populations.
Science Code(s)/Area of Science(s) Primary: 57 - Bone and Cartilage
Secondary: 03 - Carcinogenesis/Cell Transformation
Publications No publications associated with this grant
Program Officer Thaddeus Schug
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