Dysfunctional skeletal muscle communication in arsenic-promoted cardiometabolic disease

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.

Grant Number: 5R01ES033519-05
NIH Institute/Center: NIH
Principal Investigator: Aaron Barchowsky