Autophagy Modulation Is Context-Dependent and Has Muscle-Specific Signatures

Wangkuk Son; Maximiliano Espinosa-Ramírez; Ryan Allen; Vitor A. Lira

doi:10.1152/physiol.2026.41.S1.2346841

Abstract only The autophagy-lysosome system is critical for the maintenance of muscle integrity. However, whether different types of catabolic stimuli elicit unique activation patterns of autophagy in muscle remains unclear. Unc-51-like kinase 1 (ULK1) and 2 (ULK2) coordinate the initiation of selective protein degradation via (macro)autophagy. Here, we compared the effects of disuse, fasting, and aerobic exercise on ULK1/2 signaling and the autophagy process in skeletal muscle, and hypothesized that: a) ULK1/2 is required for autophagy stimulation in these conditions; and b) ULK1/2 phosphorylation patterns and downstream signaling are context-dependent. Wild-type (WT) and skeletal muscle-specific ULK1/2 knockout (Ulk1/2skmDKO) mice underwent unilateral hindlimb immobilization (3-7 days), fasting (15 h), or an aerobic exercise bout (90 min). Tibialis anterior (TA; disuse, fasting and exercise), soleus (SOL; fasting and exercise), and plantaris (PL; fasting and exercise) muscles were analyzed. Induction of autophagy was attenuated in Ulk1/2skmDKO across all conditions and muscles. However, key autophagy-related signaling steps assumed condition- and muscle-specific patterns. During immobilization, autophagy was induced in WT TA muscle, and was associated with higher AMPK (T172), a known stimulator of ULK1/2 signaling, without changes in key ULK1 phosphorylation sites (S555, S757, S317) or in the ULK1/2 downstream targets Beclin 1 (S30), ATG14 (S29), and ATG16 (S249). Fasting induced autophagy in the WT SOL and PL, but not the TA. This was paralleled by higher AMPK (T172) in most muscles, but again without changes in ULK1 phosphorylation sites, or in ULK1/2 targets. After exercise, AMPK (T172) was higher, and autophagy was induced in all WT muscles, but once more without changes in ULK1 phosphorylation. ULK1/2 downstream targets did not change in WT TA, but we observed higher levels of Beclin 1 (S30) and ATG16 (S249) in SOL and PL, while ATG14 (S29) was higher only in SOL. Collectively, these findings indicate that ULK1/2 play an essential role in modulating skeletal muscle autophagy across diverse stimuli. This correlates with AMPK activation, but not with changes at AMPK-targeted sites at ULK1. In addition, autophagy-related signals downstream of ULK1/2 are context-dependent and appear to involve specific signatures across different muscles. Funding Source: Supported by NIH R56AG080101. This abstract was presented at the American Physiology Summit 2026 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.

Autophagy Modulation Is Context-Dependent and Has Muscle-Specific Signatures

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