While cancer-induced skeletal muscle wasting has been widely investigated, the drivers of cancer-induced muscle functional decrements are only beginning to be understood. Decreased muscle function impacts cancer patient quality of life and health status, and several potential therapeutics have failed in clinical trials due to a lack of functional improvement. Furthermore, systemic inflammation and intrinsic inflammatory signaling's role in the cachectic disruption of muscle function requires further investigation. We examined skeletal muscle functional properties during cancer cachexia and determined their relationship to systemic and intrinsic cachexia indices. Male ApcMin/+ (MIN) mice were stratified by percent body weight loss into weight stable (WS; <5% loss) or cachectic (CX; >5% loss). Age-matched C57BL/6 littermates served as controls. Tibialis anterior (TA) twitch properties, tetanic force, and fatigability were examined in situ. TA protein and mRNA expression were examined in the nonstimulated leg. CX decreased muscle mass, tetanic force (Po), and specific tetanic force (sPo). Whole body and muscle fatigability were increased in WS and CX. CX had slower contraction rates, +dP/d t and -dP/d t, which were inversely associated with muscle signal transducer and activator of transcription 3 ( STAT3) and p65 activation. STAT3 and p65 activation were also inversely associated with Po. However, STAT3 was not related to sPo or fatigue. Muscle suppressor of cytokine signaling 3 mRNA expression was negatively associated with TA weight, Po, and sPo but not fatigue. Our study demonstrates that multiple functional deficits that occur with cancer cachexia are associated with increased muscle inflammatory signaling. Notably, muscle fatigability is increased in the MIN mouse before cachexia development. NEW & NOTEWORTHY Recent studies have identified decrements in skeletal muscle function during cachexia. We have extended these studies by directly relating decrements in muscle function to established cachexia indices. Our results demonstrate that a slow-fatigable contractile phenotype is developed during the progression of cachexia that coincides with increased muscle inflammatory signaling. Furthermore, regression analysis identified predictors of cancer-induced muscle dysfunction. Last, we report the novel finding that whole body and muscle fatigability were increased before cachexia development.
Keywords: fatigability; interleukin-6; muscle fatigue; muscle force; muscle twitch characteristics.