The autophagy inhibitor NSC185058 suppresses mTORC1-mediated protein anabolism in cultured skeletal muscle.

The mammalian target of rapamycin (mTOR), and specifically the mTOR complex 1 (mTORC1) is the central regulator of anabolism in skeletal muscle. Among the many functions of this kinase complex is the inhibition of the catabolic process of autophagy; however, less work has been done in investigating the role of autophagy in regulating mTORC1 signaling. Using an in vitro model to better understand the pathways involved, we activated mTORC1 by several different means (growth factors, leucine supplementation, or muscle contraction), alone or with the autophagy inhibitor NSC185058. We found that inhibiting autophagy with NSC185058 suppresses mTORC1 activity, preventing any increase in cellular protein anabolism. These decrements were the direct result of action on the mTORC1 kinase, which we demonstrate, for the first time, cannot function when autophagy is inhibited by NSC185058. Our results indicate that, far from being a matter of unidirectional action, the relationship between mTORC1 and the autophagic cascade is more nuanced, with autophagy serving as an mTORC1 input, and mTORC1 inhibition of autophagy as a form of homeostatic feedback to regulate anabolic signaling. Future studies of cellular metabolism will have to consider this fundamental intertwining of protein anabolism and catabolism, and how it ultimately serves to regulate muscle proteostasis.

Anabolic responses to acute and chronic resistance exercise are enhanced when combined with aquatic treadmill exercise.

Aquatic treadmill (ATM) running may simultaneously promote aerobic fitness and enhance muscle growth when combined with resistance training (RT) compared with land-treadmill (LTM) running. Therefore, we examined acute and chronic physiological responses to RT, concurrent RT-LTM, and concurrent RT-ATM. Forty-seven untrained volunteers (men: n = 23, 37 ± 11 yr, 29.6 ± 4.6 kg/m(2); women: n = 24, 38 ± 12 yr, 27.53 ± 6.4 kg/m(2)) from the general population were tested for V̇o2max, body composition, and strength before and after training. All groups performed 12 wk of RT (2 wk, 3 × 8-12 sets at 60 to approximately 80% 1-repetition maximum). The RT-LTM and RT-ATM groups also performed 12 wk of LTM or ATM training (2 wk immediately post-RT and 1 wk in isolation, 60-85% V̇o2max, 250-500 kcal/session). Additionally, 25 subjects volunteered for muscle biopsy prior to and 24 h post-acute exercise before and after training. Stable isotope labeling (70% (2)H2O, 3 ml/kg) was utilized to quantify 24 h post-exercise myofibrillar fractional synthesis rates (myoFSR). Mixed-model ANOVA revealed that RT-ATM but not RT-LTM training produced greater chronic increases in lean mass than RT alone (P < 0.05). RT-LTM training was found to elicit the greatest decreases in percent body fat (-2.79%, P < 0.05). In the untrained state, acute RT-ATM exercise elicited higher 24-h myoFSRs compared with RT (+5.68%/day, P < 0.01) and RT-LTM (+4.08%/day, P < 0.05). Concurrent RT-ATM exercise and training elicit greater skeletal muscle anabolism than RT alone or RT-LTM.