title: Arsenic Promotes NF-Κb-Mediated Fibroblast Dysfunction and Matrix Remodeling to Impair Muscle Stem Cell Function.
abstract: Arsenic is a global health hazard that impacts over 140 million individuals worldwide. Epidemiological studies reveal prominent muscle dysfunction and mobility declines following arsenic exposure; yet, mechanisms underlying such declines are unknown. The objective of this study was to test the novel hypothesis that arsenic drives a maladaptive fibroblast phenotype to promote pathogenic myomatrix remodeling and compromise the muscle stem (satellite) cell (MuSC) niche. Mice were exposed to environmentally relevant levels of arsenic in drinking water before receiving a local muscle injury. Arsenic-exposed muscles displayed pathogenic matrix remodeling, defective myofiber regeneration and impaired functional recovery, relative to controls. When naïve human MuSCs were seeded onto three-dimensional decellularized muscle constructs derived from arsenic-exposed muscles, cells displayed an increased fibrogenic conversion and decreased myogenicity, compared with cells seeded onto control constructs. Consistent with myomatrix alterations, fibroblasts isolated from arsenic-exposed muscle displayed sustained expression of matrix remodeling genes, the majority of which were mediated by NF-κB. Inhibition of NF-κB during arsenic exposure preserved normal myofiber structure and functional recovery after injury, suggesting that NF-κB signaling serves as an important mechanism of action for the deleterious effects of arsenic on tissue healing. Taken together, the results from this study implicate myomatrix biophysical and/or biochemical characteristics as culprits in arsenic-induced MuSC dysfunction and impaired muscle regeneration. It is anticipated that these findings may aid in the development of strategies to prevent or revert the effects of arsenic on tissue healing and, more broadly, provide insight into the influence of the native myomatrix on stem cell behavior.
authors.affiliation: Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Changqing
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Ferrari
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Beezhold
authors.affiliation: Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Stearns-Reider
authors.affiliation: Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: D'Amore
authors.affiliation: Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Haschak
authors.affiliation: Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Stolz
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Robbins
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.|Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Barchowsky
authors.affiliation: Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.|McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.|Department of Physical Therapy, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Fabrisia
authors.initials: F
authors.lastname: Ambrosio
mesh_terms: D000818:Animals; D001151:Arsenic / Q000633:toxicity; D005347:Fibroblasts / Q000187:drug effects; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006801:Humans; D051379:Mice; D024510:Muscle Development / Q000187:drug effects* / Q000235:genetics; D032446:Myoblasts / Q000187:drug effects / Q000473:pathology; D016328:NF-kappa B / Q000096:biosynthesis* / Q000235:genetics; D012038:Regeneration / Q000187:drug effects; D032496:Satellite Cells, Skeletal Muscle / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects*; D051996:Transcription Factor RelA / Q000096:biosynthesis / Q000235:genetics
chemical_list: D016328:NF-kappa B; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D001151:Arsenic
keywords: Muscle stem cells; Myofibroblast; Myogenesis; Skeletal muscle; arsenic