Endo Y, Baldino K, Li B, Zhang Y, Sakthivel D, MacArthur M, Panayi AC, Kip P, Spencer DJ, Jasuja R, Bagchi D, Bhasin S, Nuutila K, Neppl RL, Wagers AJ, Sinha I. 2020. Loss of ARNT in skeletal muscle limits muscle regeneration in aging. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 34(12):16086-16104. Pubmed: 33064329 DOI:10.1096/fj.202000761RR


The ability of skeletal muscle to regenerate declines significantly with aging. The expression of aryl hydrocarbon receptor nuclear translocator (ARNT), a critical component of the hypoxia signaling pathway, was less abundant in skeletal muscle of old (23-25 months old) mice. This loss of ARNT was associated with decreased levels of Notch1 intracellular domain (N1ICD) and impaired regenerative response to injury in comparison to young (2-3 months old) mice. Knockdown of ARNT in a primary muscle cell line impaired differentiation in vitro. Skeletal muscle-specific ARNT deletion in young mice resulted in decreased levels of whole muscle N1ICD and limited muscle regeneration. Administration of a systemic hypoxia pathway activator (ML228), which simulates the actions of ARNT, rescued skeletal muscle regeneration in both old and ARNT-deleted mice. These results suggest that the loss of ARNT in skeletal muscle is partially responsible for diminished myogenic potential in aging and activation of hypoxia signaling holds promise for rescuing regenerative activity in old muscle.
© 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.

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Amy Wagers seeks to change the way we repair our tissues after an injury. Her research focuses on defining the factors and mechanisms that regulate the migration, expansion, and regenerative potential of adult blood-forming and muscle-forming stem cells.

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