Arsenic is an odorless and tasteless semi-metal that contaminates drinking water supplies from natural deposits in the earth. It is estimated that almost 3.7 million individuals in the US, and over 140 million individuals worldwide, are exposed regularly to drinking water that exceed government arsenic standards. Increasing attention has been recently paid to the declines in functional mobility resulting from chronic arsenic exposure, which we now understand to pose a significant risk for causing skeletal muscle myopathies and atrophy, impairments that are among the greatest factors contributing to declines in functional mobility and strong predictors of mortality. However, many questions of the health impacts of environmental exposures throughout life remain, including the underlying mechanisms by which exposures negatively impact the cellular microenvironment, stem cell phenotype and, ultimately, tissue maintenance and healing capacity. There is a need to know whether and how environmental toxicants affect tissue maintenance and adult stem cell behavior and it is important to resolve how stem cell vulnerability to environmental contaminants affects the ability of otherwise healthy tissues to respond to acute injury. It is also critical to identify mechanisms of impairment in designing strategies and policies to prevent or reduce injury. The objective of this proposal is to elucidate mechanisms for arsenic-stimulated alteration of transcriptional circuitries that disrupt intra- and inter-cellular communication within the niche and compromise muscle structural integrity. We propose two specific aims to test our central hypothesis that arsenic stimulates fibroblast- mediated pathogenic matrix alterations, resulting in stem cell dysfunction and, ultimately, impaired wound repair after injury.
In Specific Aim 1, we will test th hypothesis that exposure to commonly encountered levels of arsenic in drinking water promotes pathologic matrix remodeling to impair muscle stem cell function and regenerative capacity.
In Specific Aim 2, we will test the hypothesis that arsenic dysregulates fibroblast activation, drivin an impaired muscle stem cell function and tissue repair response after injury. Success in these aims will both increase our understanding of the pathogenesis of arsenic-induced clinical symptoms of myasthenia, and will elucidate skeletal muscle micro environmental factors controlling stem cell declines. The long-term goal is to create prevention and/or intervention strategies to improve health outcomes of individuals living in arsenic-endemic areas.
Environmental toxicants, such as arsenic in drinking water, pose a significant and commonly encountered risk for causing skeletal muscle myopathies and atrophy; impairments that are among the greatest factors contributing to declines in functional mobility and strong predictors of mortality. Negative impact of chronic exposure to arsenic or other environmental toxicants on muscle stem cell biology and their local microenvironment represents an important pathogenic mechanism for reducing the capacity of these cells to maintain and regenerate muscle tissue. An improved understanding of arsenical effects on myofiber function and stem cell regenerative capacity in the etiology of arsenic-induced muscle weakness and fatigue will provide strategies for improving outcomes in patients in arsenic-endemic areas and for increasing basic knowledge of mechanisms through which environmental exposures impair stem cell function.
|Stearns-Reider, Kristen M; D'Amore, Antonio; Beezhold, Kevin et al. (2017) Aging of the skeletal muscle extracellular matrix drives a stem cell fibrogenic conversion. Aging Cell 16:518-528|
|Zhang, Changqing; Ferrari, Ricardo; Beezhold, Kevin et al. (2016) Arsenic Promotes NF-?b-Mediated Fibroblast Dysfunction and Matrix Remodeling to Impair Muscle Stem Cell Function. Stem Cells 34:732-42|