Abstract
Age-associated muscle atrophy is a debilitating condition associated with loss of muscle mass and function with age that contributes to limitation of mobility and locomotion. However, the underlying mechanisms of how intrinsic muscle changes with age are largely unknown. Here we report that, with age, Mind bomb-1 (Mib1) plays important role in skeletal muscle maintenance via proteasomal degradation-dependent regulation of α-actinin 3 (Actn3). The disruption of Mib1 in myofibers (Mib1ΔMF) results in alteration of type 2 glycolytic myofibers, muscle atrophy, impaired muscle function, and Actn3 accumulation. After chronic exercise, Mib1ΔMF mice show muscle atrophy even at young age. However, when Actn3 level is downregulated, chronic exercise-induced muscle atrophy is ameliorated. Importantly, the Mib1 and Actn3 levels show clinical relevance in human skeletal muscles accompanied by decrease in skeletal muscle function with age. Together, these findings reveal the significance of the Mib1-Actn3 axis in skeletal muscle maintenance with age and suggest the therapeutic potential for the treatment or amelioration of age-related muscle atrophy.
Highlights
Jieon Park 1, Inkuk Park 1, Hyerim Park 1, Kyusang Yoo 1, Joonwoo Rhee 1, Jung-Wee Park 2, Yong Chan Ha2 & Young-Yun Kong 1✉
This study uncovered the crosstalk between Mib[1] and skeletal muscle maintenance with age, which paves the way toward the understanding of how the loss of Mib[1] concomitantly contributes to age-associated muscle atrophy, and subsequent loss and/or atrophy of type 2 glycolytic myofibers
Mib[1] plays a significant role in the maintenance of skeletal muscle, type 2 glycolytic myofibers, by directly binding to and ubiquitinating Actn[3], which is predominantly expressed in type 2 glycolytic myofibers
Summary
Jieon Park 1, Inkuk Park 1, Hyerim Park 1, Kyusang Yoo 1, Joonwoo Rhee 1, Jung-Wee Park 2, Yong Chan Ha2 & Young-Yun Kong 1✉. The disruption of Mib[1] in myofibers (Mib1ΔMF) results in alteration of type 2 glycolytic myofibers, muscle atrophy, impaired muscle function, and Actn[3] accumulation. The Mib[1] and Actn[3] levels show clinical relevance in human skeletal muscles accompanied by decrease in skeletal muscle function with age. Together, these findings reveal the significance of the Mib1-Actn[3] axis in skeletal muscle maintenance with age and suggest the therapeutic potential for the treatment or amelioration of age-related muscle atrophy.
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