Inflammatory Signaling Regulation of Eccentric Contractioninduced Muscle Protein Synthesis in Cachectic Skeletal Muscle
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Eccentric muscle contractions (ECC) induce growth that is associated with increased protein synthesis regulated by mTORC1. While disrupted muscle protein turnover occurs during cancer cachexia, cachectic muscle's capacity to respond to ECC is not well understood. Repeated ECC bouts during the progression of cachexia can attenuate muscle mass loss, reduce muscle inflammatory signaling, and decrease AMPK activation. However, cachectic muscle's ability to induce protein synthesis through mTORC1 has not examined. Therefore, we examined if cancerinduced muscle inflammatory signaling involving STAT3 and NFkB could disrupt ECCinduced protein synthesis. Either pharmacological (PDTC, a STAT3/NFkB inhibitor) or nonpharmacological (ECC training) treatments were used to alter muscle inflammatory signaling. mTORC1 signaling and protein synthesis was examined 3h after a single bout of ECC in C57BL/6 (B6; N=9) and cachectic ApcMin/+ (MIN; N=9; 16% BW loss) mice. A subset of MIN mice (N=6; 17% BW loss) also received a single PDTC injection 24h prior to acute muscle contraction. The acute response after ECC training (8 bouts over 2 weeks) in C57BL/6 (N=8) and MIN mice (N=9; 15% BW loss) was also examined. In all experiments the left tibialis anterior (TA) performed ECC while the right TA served as intraanimal control. Cachexia decreased TA muscle mass, mTORC1 signaling, and protein synthesis when compared to B6 controls. While the ECC induction of p70S6K(T389) phosphorylation was not attenuated by cachexia, the protein synthesis induction by ECC remained suppressed compared to B6 controls. Inhibition of STAT3/NFkB signaling increased basal muscle protein synthesis in MIN mice, which was further enhanced by ECC. The acute ECC induction of muscle protein synthesis was not altered by training. These data demonstrate that basal muscle protein synthesis in cachectic muscle is regulated by muscle inflammatory signaling. However, cachectic muscle inflammatory signaling does not alter the ECC induction of mTORC1 signaling and muscle protein synthesis.Support or Funding InformationSupported by NCI R01CA121249 (JAC) and an ACSM Foundation Research Grant (JPH).
