STAT3 Regulation In Cachectic Skeletal Muscle After Repeated Eccentric Contractions

Abstract

Introduction The cachectic muscle's response to multiple bouts of eccentric contractions (ECC) has not been examined. We examined if 2 weeks of repeated ECC training could alter STAT3 regulation in cachectic muscle. Methods Male C57BL/6 (B6; N=9) and ApcMin/+ mice were subjected to 7 bouts of high-frequency electrical stimulation (100 Hz, 6-12V, 10 sets of 6 repetitions) over 2 weeks. The left tibialis anterior (TA) muscle performed ECC while the right TA served as an intra-animal control. ApcMin/+ mice were stratified into mild (7%; N=5) and severe (16% loss; N=4) cachexia based on the percentage of body weight loss at the end of the study. Results ApcMin/+ mice had smaller control TA muscle mass (-26%; P<.01) and type IIA and IIB myofiber cross-sectional area (CSA) compared to B6 mice. Cachexia increased control TA muscle STAT3 phosphorylation (9-fold; P<.05), p42/44 MAPK phosphorylation (8-fold; P<.05), and Atrogin-1 protein expression (9-fold; P<.05). Independent of cachexia ECC increased TA muscle mass and type IIA and IIB myofiber CSA. ECC had no effect on TA muscle STAT3 phosphorylation in mildly cachectic mice, but there was a 30% reduction (P<.01) in severely cachectic mice. ECC had no effect on muscle p42/p44 MAPK phosphorylation in ApcMin/+ mice. The induction of Atrogin-1 protein expression was attenuated 31% (P<.01) by ECC in severely cachectic mice. Conclusion These results suggest that repeated bouts of ECC can alter cachexia-induced muscle signaling. The contraction-induced regulation of STAT3 signaling during cachexia progression warrants further investigation. Supported by NIH/NCI R01CA121249 to JAC.