The Role of Extracellular Matrix Communication in Arsenic-Impaired Skeletal Muscle Stem Cell Determination

Hundreds of millions of individuals worldwide are exposed daily to pathogenic levels of arsenic in the environment. Anthropogenic exposures have caused morbidity, disease, and fatalities through millennia. Chronic arsenic exposures increase risks of cancer and non-cancer diseases, of which cardiovascular and metabolic diseases carry the most considerable disease burden. There is increasing realization that declines in skeletal muscle homeostasis and compositional quality underlie the etiology of cardiovascular and metabolic disease risk. However, the contribution and mechanisms of environmental factors, such as arsenic exposure, in promoting these declines are relatively unknown. Thus, this dissertation sought to fill this significant knowledge gap by investigating the hypothesis that arsenic promotes muscle dysfunction by disrupting intercellular communication within the muscle progenitor cell niche that is critical to muscle maintenance and determination of muscle composition. The studies used in vivo arsenic exposures with interventions combined with ex vivo cell culture experiments to demonstrate that arsenic imparts a dysfunctional memory of intercellular communication into the muscle extracellular matrix (ECM) that disrupts the differentiation fate of myogenic and fibro-adipogenic progenitor cells following injury. Human muscle progenitor cells exposed to low levels of arsenic or to ECM elaborated by connective tissue fibroblasts exposed to arsenic in vivo were misdirected from their myogenic fate to either fibrogenic or adipogenic determination. The studies found that arsenic-directed Notch1 signaling, a master regulator of intercellular communication and cell fate, in the ECM promoted the fibro-adipogenic determination of the progenitor cells. Importantly, in vivo intervention with SS-31, a mitochondrial protective peptide, or ex vivo pharmacological inhibition of Notch activation reversed the impaired tissue regeneration and dysfunctional cell fate determination caused by arsenic exposures. These studies identify the connective tissue fibroblast mitochondria as a target of arsenic-promoted muscle pathogenesis. The findings may have a significant impact on public health as they would reveal a plausible therapeutic intervention that may reduce the severity and burden of disease caused by arsenic exposures