Muscle Inflammatory Signaling's Contribution to Cancer Cachexiainduced Decrements in Muscle Function
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Although skeletal muscle mass loss defines cachexia, changes in muscle function related to strength loss and increased fatigue can further impact life quality and health status. However, there are gaps in our understanding of the cachectic environment that regulates muscle function. While cancerinduced inflammatory signaling can disrupt skeletal muscle protein turnover regulation, inflammatory signaling's contribution to altered cachectic muscle function remains to be determined. Therefore, the purpose of this study was to determine cancer cachexiainduced inflammatory signaling's contribution to decrements in the functional properties of skeletal muscle. Two preclinical models of cancer cachexia were examined; the ApcMin/+ (MIN) and Lewis lung carcinoma (LLC) implanted mice. The MIN mouse has a nonsense mutation on the Apc gene and develop intestinal tumors by 12 weeks of age resulting in a cachectic phenotype by 20 weeks of age. 106 LLC tumor cells were injected into the flank and mice develop severe cachexia within 5 weeks. Skeletal muscle function and inflammatory signaling was examined in male, MIN (20wk, >5% BW loss) and LLC (13wk, 30 days' post injection) mice. Tibialis anterior (TA) twitch properties, tetanic force and fatigue were examined insitu to maintain intact nerve and blood supply. LLC and MIN decreased TA mass and twitch characteristics compared to their respective controls. LLC and MIN increased 1/2 relaxation time ( RT), and this change was independent to altered twitch tension. LLC (33%) and MIN (41%) decreased tetanic force. Interestingly, only MIN decreased specific tetanic force (13%). TA fatigability was increased in both MIN (22%) and LLC (11%). MIN and LLC increased muscle STAT3 and p65 phosphorylation. The induction of STAT3 and p65 phosphorylation was inversely related to absolute force (R=0.76, p<0.0001), but only p65 phosphorylation was inversely related to specific tension (R=0.71, p=0.002). Inflammation was not associated with increased fatigue. There was a trend for STAT3 phosphorylation to be related too increased RT (R=0.46, p=0.07). Cachexia progression altered several skeletal muscle functional properties in 2 distinct cancer cachexia models. While decrements in force production were associated with muscle inflammatory signaling, fatigue susceptibility was not.Support or Funding InformationR01CA12124907
