Skeletal muscle ULK1 and ULK2 modulate protein synthesis impacting fiber size

Abstract

Maintenance of skeletal muscle homeostasis is largely influenced by the processes of protein synthesis and degradation. However, the regulation of these processes remains incompletely understood particularly in a tissue or cell type-specific manner. We have previously demonstrated that Unc-51 like autophagy activating kinases 1 and 2 (Ulk1/2) are among the top 5 mostly enriched putative autophagy genes in skeletal muscle when compared to >90 other mouse tissues and cell lines (Fuqua et al., FASEB J, 2019). However, because protein kinases commonly have several downstream targets, here we hypothesized that skeletal muscle ULK1 and ULK2 redundantly modulate other important cellular processes. To begin to address this question, we generated mice with skeletal muscle-specific knockout of ULK1 and ULK2 (i.e., ULK1/2 skmDKO) and studied those at different ages. Muscle basal autophagy flux was impaired in ULK1/2 skmDKO mice. However, contrary to other models of autophagy impairment, which commonly leads to muscle atrophy, adult ULK1/2 skmDKO mice had increased muscle size (15-25%, P≤0.01). Hypertrophy occurred in all fiber types (6-20% increase in fiber diameter, P≤0.05) and in response to an acute (4-week) deficiency of ULK1/2 (via electroporations of plasmids encoding ULK1/2miR), where TA fiber diameter increased by 9% (p<0.05). Further studies using D2O labeling and cellular fractionation revealed that ULK1/2 skmDKO mice have increased myofibrillar protein synthesis rates (~5%/day, p<0.05). Examination of the molecular mechanisms involved suggests that ULK1/2 skmDKO mice have enhanced mTORC1-dependent signaling, particularly in the fed state. Altogether, our findings reveal for the first time that ULK1 and ULK2 collectively stimulate protein degradation and inhibit protein synthesis in skeletal muscle potentially impacting muscle mass and function in conditions of muscle atrophy and hypertrophy. Supported by the University of Iowa Fraternal Order of Eagles Diabetes Research Center (UIowa FOEDRC). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.