delayed recovery of skeletal muscle mass following hindlimb immobilization in mtor heterozygous mice延迟复苏后骨骼肌质量下肢固定在mtor杂合的老鼠.pdfVIP

Delayed Recovery of Skeletal Muscle Mass following Hindlimb Immobilization in mTOR Heterozygous Mice Susan M. Lang, Abid A. Kazi, Ly Hong-Brown, Charles H. Lang* Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America Abstract The present study addressed the hypothesis that reducing mTOR, as seen in mTOR heterozygous (+/ 2) mice, would exaggerate the changes in protein synthesis and degradation observed during hindlimb immobilization as well as impair normal muscle regrowth during the recovery period. Atrophy was produced by unilateral hindlimb immobilization and data compared to the contralateral gastrocnemius. In wild-type (WT) mice, the gradual loss of muscle mass plateaued by day 7. This response was associated with a reduction in basal protein synthesis and development of leucine resistance. Proteasome activity was consistently elevated, but atrogin-1 and MuRF1 mRNAs were only transiently increased returning to basal values by day 7. When assessed 7 days after immobilization, the decreased muscle mass and protein synthesis and increased proteasome activity did not differ between WT and mTOR+/ 2 mice. Moreover, the muscle inflammatory cytokine response did not differ between groups. After 10 days of recovery, WT mice showed no decrement in muscle mass, and this accretion resulted from a sustained increase in protein synthesis and a normalization of proteasome activity. In contrast, mTOR+/ 2 mice failed to fully replete muscle mass at this time, a defect caused by the lack of a compensatory increase in protein synthesis. The delayed muscle regrowth of the previously immobilized muscle in the mTOR+/ 2 mice was associated with a decreased raptorN4EBP1 and increased raptorNDeptor binding. Slowed regrowth was also associated with a sustained