Trx1-attenuated Endoplasmic Reticulum Stress is Involved in Exercise-inhibited Loss of Skeletal Muscle Mass after Myocardial Infarction

Objective: To investigate the mechanism of exercise in inhibiting the loss of skeletal muscle mass after myocardial infarction(MI) by regulating thioredoxin1(Trx1) expression and inhibiting oxidative stress and endoplasmic reticulum stress(ERS).Methods: 3-month-old C57B6 L mice were randomly divided into three groups: Sham group(Sham, n=8), myocardial infarction group(MI, n=8) and MI+aerobic exercise group(ME, n=8). Mice in the MI and ME groups were ligated the left anterior descending coronary artery to establish the MI model, and mice in the ME group were finished a six-week aerobic exercise training program from the second week after surgery. After training, the ratio of tibialis anterior muscle(TA) weight/body weight, the crosssectional area of the muscle cells, reactive oxygen species(ROS) level and antioxidant ability, the protein expression of MuRF1,MAFbx, Trx1, TXNIP and ERS-related proteins and cell apoptosis were measured. C2C12 myoblasts were treated with H₂O₂ and intervened with recombinant Trx1 protein(TXN) or/and Trx1 inhibitor PX-12. ERS-related proteins expression and cell apoptosis were detected in C2 C12 myoblasts. Results: Compared to the Sham group, the ratio of TA weight/body weight and the crosssectional area of the muscle cells were reduced in MI group, and the Trx1 protein expression and SOD activity were decreased as well, but the levels of ROS and MDA as well as the expression of MuRF1, MAFbx, TXNIP and ERS related protein and cell apoptosis were increased. Compared to the MI group, the ME group increased the ratio of TA weight/body weight and the crosssectional area of the muscle cells, reduced the levels of ROS and MDA as well as the expressions of MuRF1, MAFbx, TXNIP and ERS related protein and cell apoptosis level, increased SOD activity and the expression of Trx1 and GRP78 after aerobic exercise training. H₂O₂ up-regulated the expression of TXNIP, ATF6, GRP78, CHOP and cleaved caspase12 in C2C12 myoblasts and induced cell apoptosis. In H₂O₂-treated cells, PX-12 intervention aggravated C2C12 myoblasts apoptosis, while TXN intervention downregulated the expression of ATF6, GRP78 and CHOP protein and reduced apoptosis levels, in addition, PX-12 partly blocked the protective effects of TXN. Conclusion: Aerobic exercise inhibits MI-induced loss of skeletal muscle mass, which related to the decrease of protein degradation, up-regulation of Trx1 expression, inhibition of ERS and cell apoptosis. Regulation of ERS by Trx1 is one of the possible mechanisms in inhibiting cell apoptosis.