Clara L Neal, William A Kronert, Jared Rafael T Camillo, Jennifer A Suggs, Tom Huxford, Sanford I Bernstein
Aging cell 2024 JunThe molecular motor myosin is post-translationally modified in its globular head, its S2 hinge, and its thick filament domain during human skeletal muscle aging. To determine the importance of such modifications, we performed an integrative analysis of transgenic Drosophila melanogaster expressing myosin containing post-translational modification mimic mutations. We determined effects on muscle function, myofibril structure, and myosin biochemistry. Modifications in the homozygous state decreased jump muscle function by a third at 3 weeks of age and reduced indirect flight muscle function to negligible levels in young flies, with severe effects on flight muscle myofibril assembly and/or maintenance. Expression of mimic mutations in the heterozygous state or in a wild-type background yielded significant, but less severe, age-dependent effects upon flight muscle structure and function. Modification of the residue in the globular head disabled ATPase activity and in vitro actin filament motility, whereas the S2 hinge mutation reduced actin-activated ATPase activity by 30%. The rod modification diminished filament formation in vitro. The latter mutation also reduced proteostasis, as demonstrated by enhanced accumulation of polyubiquitinated proteins. Overall, we find that mutation of amino acids at sites that are chemically modified during human skeletal muscle aging can disrupt myosin ATPase, myosin filament formation, and/or proteostasis, providing a mechanistic basis for the observed muscle defects. We conclude that age-specific post-translational modifications present in human skeletal muscle are likely to act in a dominant fashion to affect muscle structure and function and may therefore be implicated in degeneration and dysfunction associated with sarcopenia. © 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.
Clara L Neal, William A Kronert, Jared Rafael T Camillo, Jennifer A Suggs, Tom Huxford, Sanford I Bernstein. Aging-affiliated post-translational modifications of skeletal muscle myosin affect biochemical properties, myofibril structure, muscle function, and proteostasis. Aging cell. 2024 Jun;23(6):e14134
PMID: 38506610
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