Lifelong Deficiency in Ulk1-Mediated Autophagy Precipitates Skeletal Muscle Aging: 566 May 29 2:30 PM - 2:45 PM

Autophagy is a cellular recycling mechanism critical for maintaining cellular homeostasis because it degrades dysfunctional organelles and proteins. Insufficient autophagy is implicated in the pathophysiology of a plethora of diseases (i.e. Type 2 diabetes, obesity, and sarcopenia) and in the process of aging across many cell types. Ulk1 is an autophagy-related protein kinase that initiates autophagy and may be particularly critical for maintaining skeletal muscle cellular homeostasis throughout life. PURPOSE: To investigate muscle health and function in an aging mouse model with a lifelong deficiency of Ulk-1-mediated autophagy. METHODS: Longitudinal measurements of in vivo ankle dorsiflexion torque of muscle-specific Ulk1 knockout mice (Ulk1 KO) and their littermates controls (LM) were performed beginning at 12 months of age. At age 22 months, mice were administered a glucose tolerance test (GTT), followed by in vitro force testing of the extensor digitorum longus (EDL) and soleus (SOL) muscles. Mice were then sacrificed and mitochondrial function was measured via oxygen consumption rates of permeabilized muscle fibers from the gastrocnemius muscle. RESULTS: Body mass did not change throughout the longitudinal force measurements (p=0.58). Ulk1 KO mice experienced a greater reduction in in vivo ankle dorsiflexion torque from age 12 months to age 22 months compared to LM mice (-50% vs. -36%, p=0.026). In vitro peak-isometric force of isolated EDL muscles was less in Ulk1 KO mice (p=0.035) compared to LM mice, but there was no difference in isolated SOL muscle force between genotypes suggesting an accelerated aging phenotype in predominately fast-twitch muscle fibers. There was no difference in the GTT between genotypes (p=0.1). Interestingly, mitochondrial respiration was greater in the Ulk1 KO mice when normalized to muscle fiber mass (p=0.001). This may reflect an accumulation of mitochondria due to Ulk1-mediated autophagy insufficiency, or an undetermined compensatory adaptation affecting mitochondrial function. CONCLUSIONS: A lifetime of insufficient Ulk-1-mediated autophagy exacerbates age-related skeletal muscle contractile dysfunction and may alter mitochondrial quality and/or quantity.