Arsenic Directs Stem Cell Fate by Imparting Notch Signaling Into the Extracellular Matrix Niche

Abstract

<jats:title>Abstract</jats:title> <jats:p>Compromise of skeletal muscle metabolism and composition may underlie the etiology of cardiovascular and metabolic disease risk from environmental arsenic exposures. We reported that arsenic impairs muscle maintenance and regeneration by inducing maladaptive mitochondrial phenotypes in muscle stem cells (MuSC), connective tissue fibroblasts (CTF), and myofibers. We also found that arsenic imparts a dysfunctional memory in the extracellular matrix (ECM) that disrupts the MuSC niche and is sufficient to favor the expansion and differentiation of fibrogenic MuSC subpopulations. To investigate the signaling mechanisms involved in imparting a dysfunctional ECM, we isolated skeletal muscle tissue and CTF from mice exposed to 0 or 100 μg/L arsenic in their drinking water for 5 weeks. ECM elaborated by arsenic-exposed CTF decreased myogenesis and increased fibrogenic/adipogenic MuSC subpopulations and differentiation. However, treating arsenic-exposed mice with SS-31, a mitochondrially targeted peptide that repairs the respiratory chain, reversed the arsenic-promoted CTF phenotype to one that elaborated an ECM supporting normal myogenic differentiation. SS-31 treatment also reversed arsenic-induced Notch1 expression, resulting in an improved muscle regeneration after injury. We found that persistent arsenic-induced CTF Notch1 expression caused the elaboration of dysfunctional ECM with increased expression of the Notch ligand DLL4. This DLL4 in the ECM was responsible for misdirecting MuSC myogenic differentiation. These data indicate that arsenic impairs muscle maintenance and regenerative capacity by targeting CTF mitochondria and mitochondrially-directed expression of dysfunctional regulators in the stem cell niche. Therapies that restore muscle cell mitochondria may effectively treat arsenic-induced skeletal muscle dysfunction and compositional decline.</jats:p>

Arsenic Secondary Methylation Capacity Is Inversely Associated with Arsenic Exposure-Related Muscle Mass Reduction

“…Experimental studies support the findings of our study. Exposure to arsenic in vivo and in vitro caused impaired functions and regeneration capacity of the muscle [ 19 , 20 , 21 , 71 ]. Exposure to arsenic causes an impairment of muscle mitochondrial morphology and functions in mice [ 19 ].…”

“…The decrease in skeletal muscle mass is also associated with pathogenic increases in the intramuscular fat (myosteatosis) [ 14 , 15 , 16 ], which leads to the promotion of IR [ 17 , 18 ]. Recently, experimental studies using animals and cultured cells have shown that arsenic affects the functions and regeneration of muscle [ 19 , 20 , 21 ]. However, less attention has been paid to the effects of arsenic exposure on the quantity and quality of the muscle in human studies.…”