Abstract
ULK1/2 inhibit skeletal muscle protein synthesis impacting fiber size
Physiology (Bethesda, Md.), Vol.40(S1)
05/2025
DOI: 10.1152/physiol.2025.40.S1.1915
Abstract
Abstract only Purpose: Skeletal muscle accounts for 20-30% of basal metabolic rate and 70-90% of insulin-stimulated glucose uptake. These features are largely influenced by the energetically demanding processes of protein synthesis and degradation. Unc-51 like autophagy activating kinases 1 and 2 (ULK1/2) have evolved from a common ancestral gene (Atg1) and are thought to have independent and redundant functions. We have previously demonstrated that ULK1 and ULK2 are enriched in skeletal muscle and that ULK2 is required for the degradation of toxic protein aggregates, whereas ULK1 is required for maximal stimulation of autophagy, a key proteolytic process for the maintenance of muscle function. Here, we investigated their poorly understood redundant role in skeletal muscle. Methods: Studies were conducted in mice with skeletal muscle-specific knockout of ULK1 and ULK2 (i.e., ULK1/2 skmDKO) at different ages and in both sexes. Acute deficiency of these proteins was achieved via electroporations of plasmids encoding specific microRNAs into the TA muscle of wild-type mice. Results: Muscle basal autophagy flux was impaired in ULK1/2 skmDKO mice. However, contrary to other models of autophagy impairment that commonly lead to muscle atrophy, these mice presented increased muscle size (15-25% in males; 9-27% in females). In males, hypertrophy occurred in all fiber types, whereas in females, hypertrophy was observed in all fiber types except for type IIx in the soleus muscle. Hypertrophy also occurred in response to a 4-week deficiency of ULK1/2 in adult muscle (9%) indicating that this modulation is not developmentally determined. Additionally, ULK1/2 skmDKO mice had increased rates of sarcomeric protein synthesis (~5%/day). Conclusions: Altogether, our findings reveal for the first time that ULK1 and ULK2 are fundamental kinases collectively modulating protein metabolism in skeletal muscle by not only stimulating autophagy but also inhibiting protein synthesis. Supported by NIH R56AG080101 to VAL. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Details
- Title: Subtitle
- ULK1/2 inhibit skeletal muscle protein synthesis impacting fiber size
- Creators
- Wangkuk Son - University of IowaJordan Fuqua - University of IowaMatthew Harris - University of IowaRyan Allen - University of IowaAna Kronemberger - University of IowaLuis De Soursa - University of IowaSue Bodine - University of IowaBenjamin Miller - Oklahoma Medical Research FoundationLeonid Zingman - University of IowaVitor Lira - University of Iowa
- Resource Type
- Abstract
- Publication Details
- Physiology (Bethesda, Md.), Vol.40(S1)
- DOI
- 10.1152/physiol.2025.40.S1.1915
- ISSN
- 1548-9213
- eISSN
- 1548-9221
- Publisher
- AMER PHYSIOLOGICAL SOC
- Grant note
- NIH: R56AG080101
Supported by NIH R56AG080101 to VAL.
- Language
- English
- Date published
- 05/2025
- Academic Unit
- Dental Research; Health, Sport, and Human Physiology ; Internal Medicine
- Record Identifier
- 9984843745902771
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