Jerson G. Cadenas

Resistance exercise increases AMPK activity and reduces 4E‐BP1 phosphorylation and protein synthesis in human skeletal muscle

Resistance exercise is a potent stimulator of muscle protein synthesis and muscle cell growth, with the increase in protein synthesis being detected within 2–3 h post‐exercise and remaining elevated for up to 48 h. However, during exercise, muscle protein synthesis is inhibited. An increase in AMP‐activated protein kinase (AMPK) activity has recently been shown to decrease mammalian target of rapamycin (mTOR) signalling to key regulators of translation initiation. We hypothesized that the cellular mechanism for the inhibition of muscle protein synthesis during an acute bout of resistance exercise in humans would be associated with an activation of AMPK and an inhibition of downstream components of the mTOR pathway (4E‐BP1 and S6K1). We studied 11 subjects (seven men, four women) before, during, and for 2 h following a bout of resistance exercise. Muscle biopsy specimens were collected at each time point from the vastus lateralis. We utilized immunoprecipitation and immunoblotting methods to measure muscle AMPKα2 activity, and mTOR‐associated upstream and downstream signalling proteins, and stable isotope techniques to measure muscle fractional protein synthetic rate (FSR). AMPKα2 activity (pmol min−1 (mg protein)−1) at baseline was 1.7 ± 0.3, increased immediately post‐exercise (3.0 ± 0.6), and remained elevated at 1 h post‐exercise (P < 0.05). Muscle FSR decreased during exercise and was significantly increased at 1 and 2 h post‐exercise (P < 0.05). Phosphorylation of 4E‐BP1 at Thr37/46 was significantly reduced immediately post‐exercise (P < 0.05). We conclude that AMPK activation and a reduced phosphorylation of 4E‐BP1 may contribute to the inhibition of muscle protein synthesis during resistance exercise. However, by 1–2 h post‐exercise, muscle protein synthesis increased in association with an activation of protein kinase B, mTOR, S6K1 and eEF2.

Nutrient signalling in the regulation of human muscle protein synthesis

The mammalian target of rapamycin (mTOR) and AMP‐activated protein kinase (AMPK) are important nutrient‐ and energy‐sensing and signalling proteins in skeletal muscle. AMPK activation decreases muscle protein synthesis by inhibiting mTOR signalling to regulatory proteins associated with translation initiation and elongation. On the other hand, essential amino acids (leucine in particular) and insulin stimulate mTOR signalling and protein synthesis. We hypothesized that anabolic nutrients would be sensed by both AMPK and mTOR, resulting in an acute and potent stimulation of human skeletal muscle protein synthesis via enhanced translation initiation and elongation.

Aerobic Exercise Overcomes the Age-Related Insulin Resistance of Muscle Protein Metabolism by Improving Endothelial Function and Akt/Mammalian Target of Rapamycin Signaling

Muscle protein metabolism is resistant to insulins anabolic effect in healthy older subjects. This is associated with reduced insulin vasodilation. We hypothesized that aerobic exercise restores muscle protein anabolism in response to insulin by improving vasodilation in older subjects. We measured blood flow, endothelin-1, Akt/mammalian target of rapamycin (mTOR) signaling, and muscle protein kinetics in response to physiological local hyperinsulinemia in two groups of older subjects following a bout of aerobic exercise (EX group: aged 70 ± 2 years; 45-min treadmill walk, 70% heart rate max) or rest (CTRL group: aged 68 ± 1 years). Baseline endothelin-1 was lower and blood flow tended to be higher in the EX group, but protein kinetics was not different between groups. Insulin decreased endothelin-1 (P < 0.05) in both groups, but endothelin-1 remained higher in the CTRL group (P < 0.05) and blood flow increased only in the EX group (EX group: 3.8 ± 0.7 to 5.3 ± 0.8; CTRL group: 2.5 ± 0.2 to 2.6 ± 0.2 ml · min−1 · 100 ml leg−1). Insulin improved Akt phosphorylation in the EX group and increased mTOR/S6 kinase 1 phosphorylation and muscle protein synthesis (EX group: 49 ± 11 to 89 ± 23; CTRL group: 58 ± 8 to 57 ± 12 nmol · min−1 · 100 ml leg−1) in the EX group only (P < 0.05). Because breakdown did not change, net muscle protein balance became positive only in the EX group (P < 0.05). In conclusion, a bout of aerobic exercise restores the anabolic response of muscle proteins to insulin by improving endothelial function and Akt/mTOR signaling in older subjects.