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 ApcMin/+ (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 AMPKα1 α2 (KO) knockout mice crossed with ApcMin/+ 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 AMPKT172 , FOXOS413 , and ULK-1S555 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.