Arsenic induces sustained impairment of skeletal muscle and muscle progenitor cell ultrastructure and bioenergetics

Abstract

Over 4 million individuals in the US, and over 140 million individuals worldwide, are exposed daily to arsenic-contaminated drinking water. Human exposures can range from below the current limit of 10 µg/L to over 1 mg/L, with 100 µg/L promoting disease in a large portion of those exposed. Although increased attention has recently been paid to myopathy following arsenic exposure, the pathogenic mechanisms underlying clinical symptoms remain poorly understood. This study tested the hypothesis that arsenic induces lasting muscle mitochondrial dysfunction and impairs metabolism. When compared to non-exposed controls, mice exposed to drinking water containing 100µg/L arsenite for 5 weeks demonstrated impaired muscle function, mitochondrial myopathy, and altered oxygen consumption that were concomitant with increased mitochondrial fusion gene transcription. There was no difference in levels of inorganic arsenic or its mononomethyl- and dimethyl- metabolites between controls and exposed muscles, confirming that arsenic does not accumulate in muscle. Nevertheless, muscle progenitor cells isolated from exposed mice recapitulated the aberrant myofiber phenotype and were more resistant to oxidative stress, generated more reactive oxygen species, and displayed autophagic mitochondrial morphology, as compared to cells isolated from non-exposed mice. These pathological changes from a possible maladaptive oxidative stress response provide insight into declines in muscle functioning caused by exposure to this common environmental contaminant.

Association of Cardiometabolic Genes with Arsenic Metabolism Biomarkers in American Indian Communities: The Strong Heart Family Study (SHFS)

“…Interestingly, phosphorylation of proteins encoded by USMG5 is known to be upregulated by insulin in vivo in human skeletal cells (Meyer et al 2007). In addition, mice exposed to 100 μg/L arsenite for 5 weeks showed impaired muscle function and mitochondrial myopathy compared with controls (Ambrosio et al 2014). Confirmation, through fine mapping or sequencing as well as through functional analyses, is needed on the relevance of USMG5 to arsenic metabolism.…”

Arsenic Promotes NF-Κb-Mediated Fibroblast Dysfunction and Matrix Remodeling to Impair Muscle Stem Cell Function

“…While human exposures to As(III) in drinking water ranges from negligible amounts to 1–4 mg/l, 100 μg/l is commonly accepted as a threshold for promoting a number of diseases and in dose ranging studies we found that this exposure was near maximal in promoting vascular tissue remodeling . Our previous studies have demonstrated that these exposure levels do not cause any signs of overt lethality or changes in weight gain . All studies were approved by the Institutional Animal Care and Use Committee of the University of Pittsburgh.…”

Regulation of cyclin D1 by arsenic and microRNA inhibits adipogenesis

“…Low to moderate levels of arsenic in drinking water (10–250 ppb) cause remodeling of liver, vascular, and metabolic tissues in mice (Straub et al, 2008; Lemaire et al, 2011; Garciafigueroa et al, 2013; Ambrosio et al, 2014). In abdominal adipose tissue, arsenic exposure changed adipocyte phenotype and lipid storage capacity while also causing redistribution of fat to perivascular regions in skeletal muscle (Garciafigueroa et al, 2013).…”