Antagonistic control of myofiber size and muscle protein quality control by the ubiquitin ligase UBR4 during aging

Liam C. Hunt, Bronwen Schadeberg, Jared Stover, Benard Haugen, Vishwajeeth Pagala, Yong-Dong Wang, Jason Puglise, Elisabeth R. Barton, Junmin Peng and Fabio Demontis ()
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Liam C. Hunt: St. Jude Children’s Research Hospital
Bronwen Schadeberg: St. Jude Children’s Research Hospital
Jared Stover: St. Jude Children’s Research Hospital
Benard Haugen: St. Jude Children’s Research Hospital
Vishwajeeth Pagala: St. Jude Children’s Research Hospital
Yong-Dong Wang: St. Jude Children’s Research Hospital
Jason Puglise: University of Florida
Elisabeth R. Barton: University of Florida
Junmin Peng: St. Jude Children’s Research Hospital
Fabio Demontis: St. Jude Children’s Research Hospital

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract Sarcopenia is a degenerative condition that consists in age-induced atrophy and functional decline of skeletal muscle cells (myofibers). A common hypothesis is that inducing myofiber hypertrophy should also reinstate myofiber contractile function but such model has not been extensively tested. Here, we find that the levels of the ubiquitin ligase UBR4 increase in skeletal muscle with aging, and that UBR4 increases the proteolytic activity of the proteasome. Importantly, muscle-specific UBR4 loss rescues age-associated myofiber atrophy in mice. However, UBR4 loss reduces the muscle specific force and accelerates the decline in muscle protein quality that occurs with aging in mice. Similarly, hypertrophic signaling induced via muscle-specific loss of UBR4/poe and of ESCRT members (HGS/Hrs, STAM, USP8) that degrade ubiquitinated membrane proteins compromises muscle function and shortens lifespan in Drosophila by reducing protein quality control. Altogether, these findings indicate that these ubiquitin ligases antithetically regulate myofiber size and muscle protein quality control.

Date: 2021
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DOI: 10.1038/s41467-021-21738-8

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