Wheel running improves fasting‐induced AMPK signaling in skeletal muscle from tumor‐bearing mice

Abstract Disruptions to muscle protein turnover and metabolic regulation contribute to muscle wasting during the progression of cancer cachexia. The initiation of cachexia is also associated with decreased physical activity. While chronic muscle AMPK activation occurs during cachexia progression in Apc Min /+ (MIN) mice, a preclinical cachexia model, the understanding of muscle AMPK’s role during cachexia initiation is incomplete. Therefore, we examined if voluntary wheel exercise could improve skeletal muscle AMPK signaling in pre‐cachectic MIN mice. Next, we examined muscle AMPK’s role in aberrant catabolic signaling in response to a 12‐h fast in mice initiating cachexia. Male C57BL/6 (B6: N  = 26) and MIN ( N  = 29) mice were subjected to ad libitum feeding, 12‐h fast, or 4 wks. of wheel access and then a 12‐h fast during the initiation of cachexia. Male tamoxifen‐inducible skeletal muscle AMPKα 1 α 2 (KO) knockout mice crossed with Apc Min /+ and floxed controls were examined (WT: N  = 8, KO: N  = 8, MIN: N  = 10, MIN KO: N  = 6). Male mice underwent a 12‐h fast and the gastrocnemius muscle was analyzed. MIN gastrocnemius mass was reduced compared to B6 mice. A 12‐h fast induced MIN muscle AMPK T172 , FOXO S413 , and ULK‐1 S555 phosphorylation compared to B6. Wheel running attenuated these inductions. A 12‐h fast induced MIN muscle MuRF‐1 protein expression compared to B6 and was suppressed by wheel running. Additionally, fasting induced muscle autophagy signaling and disrupted mitochondrial quality protein expression in the MIN, which was prevented in the MIN KO. We provide evidence that increased skeletal muscle AMPK sensitivity to a 12‐h fast is an adverse event in pre‐cachectic MIN mice, and exercise can improve this regulation.