title: Arsenic induces sustained impairment of skeletal muscle and muscle progenitor cell ultrastructure and bioenergetics.
abstract: Over 4 million individuals in the United States, 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 1mg/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. Compared to nonexposed controls, mice exposed to drinking water containing 100 μg/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 were no differences in the levels of inorganic arsenic or its monomethyl 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, compared to cells isolated from nonexposed 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.
authors: Department of Physical Medicine & Rehabilitation and University of Pittsburgh, Pittsburgh, PA 15219, USA; Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA. Electronic address: ambrosiof@upmc.edu.
authors: Fabrisia
authors: F
authors: Ambrosio
authors: Department of Physical Medicine & Rehabilitation and University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors: Elke
authors: E
authors: Brown
authors: Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors: Donna
authors: D
authors: Stolz
authors: Department of Physical Medicine & Rehabilitation and University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors: Ricardo
authors: R
authors: Ferrari
authors: Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors: Bret
authors: B
authors: Goodpaster
authors: Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors: Bridget
authors: B
authors: Deasy
authors: Department of Physical Therapy, and University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors: Giovanna
authors: G
authors: Distefano
authors: Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors: Alexandra
authors: A
authors: Roperti
authors: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors: Amin
authors: A
authors: Cheikhi
authors: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors: Yesica
authors: Y
authors: Garciafigueroa
authors: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors: Aaron
authors: A
authors: Barchowsky
mesh_terms: D000818:Animals; D001151:Arsenic / Q000633:toxicity*; D001343:Autophagy; D002478:Cells, Cultured; D004734:Energy Metabolism / Q000187:drug effects*; D004781:Environmental Exposure / Q000009:adverse effects; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008931:Mitochondria, Muscle / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D009135:Muscular Diseases / Q000139:chemically induced* / Q000378:metabolism; D009210:Myofibrils / Q000473:pathology*; D018384:Oxidative Stress; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D017382:Reactive Oxygen Species; D001151:Arsenic
keywords: Free radicals; Metabolism; Mitochondria; Resistance to stress