TY - JOUR

T1 - Contraction-regulated mTORC1 and protein synthesis: Influence of AMPK and glycogen

AU - Knudsen, Jonas Roland

AU - Li, Zhencheng

AU - Persson, Kaspar W

AU - Li, Jingwen

AU - Henriquez-Olguin, Carlos

AU - Jensen, Thomas Elbenhardt

N1 - This article is protected by copyright. All rights reserved.

PY - 2020

Y1 - 2020

N2 - The mechansitic target of rapamycin complex 1 (mTORC1)‐S6K1 signalling pathway regulates muscle growth‐related protein synthesis and is antagonized by AMP‐activated protein kinase (AMPK) in multiple cell types. Resistance exercise stimulates skeletal muscle mTORC1‐S6K1 and AMPK signalling and post‐contraction protein synthesis. Glycogen inhibits AMPK and has been proposed as a pro‐anabolic stimulus. The present study aimed to investigate how muscle mTORC1‐S6K1 signalling and protein synthesis respond to resistance exercise‐mimicking contraction in the absence of AMPK and with glycogen manipulation. Resistance exercise‐mimicking unilateral in situ contraction of musculus quadriceps femoris in anaesthetized wild‐type and dominant negative α2 AMPK kinase dead transgenic (KD‐AMPK) mice, measuring muscle mTORC1 and AMPK signalling immediately (0 h) and 4 h post‐contraction, and protein‐synthesis at 4 h. Muscle glycogen manipulation by 5 day oral gavage of the glycogen phosphorylase inhibitor CP316819 and sucrose (80 g L−1) in the drinking water prior to in situ contraction. The mTORC1‐S6K1 and AMPK signalling axes were coactivated immediately post‐contraction, despite potent AMPK‐dependent Ser792 phosphorylation on the mTORC1 subunit raptor. KD‐AMPK muscles displayed normal mTORC1‐S6K1 activation at 0 h and 4 h post‐exercise, although there was impaired contraction‐stimulated protein synthesis 4 h post‐contraction. Pharmacological/dietary elevation of muscle glycogen content augmented contraction‐stimulated mTORC1‐S6K1‐S6 signalling and rescued the reduced protein synthesis‐response in KD‐AMPK to wild‐type levels. mTORC‐S6K1 signalling is not influenced by α2‐AMPK during or after intense muscle contraction. Elevated glycogen augments mTORC1‐S6K1 signalling. α2‐AMPK‐deficient KD‐AMPK mice display impaired contraction‐induced muscle protein synthesis, which can be rescued by normalizing muscle glycogen content.

AB - The mechansitic target of rapamycin complex 1 (mTORC1)‐S6K1 signalling pathway regulates muscle growth‐related protein synthesis and is antagonized by AMP‐activated protein kinase (AMPK) in multiple cell types. Resistance exercise stimulates skeletal muscle mTORC1‐S6K1 and AMPK signalling and post‐contraction protein synthesis. Glycogen inhibits AMPK and has been proposed as a pro‐anabolic stimulus. The present study aimed to investigate how muscle mTORC1‐S6K1 signalling and protein synthesis respond to resistance exercise‐mimicking contraction in the absence of AMPK and with glycogen manipulation. Resistance exercise‐mimicking unilateral in situ contraction of musculus quadriceps femoris in anaesthetized wild‐type and dominant negative α2 AMPK kinase dead transgenic (KD‐AMPK) mice, measuring muscle mTORC1 and AMPK signalling immediately (0 h) and 4 h post‐contraction, and protein‐synthesis at 4 h. Muscle glycogen manipulation by 5 day oral gavage of the glycogen phosphorylase inhibitor CP316819 and sucrose (80 g L−1) in the drinking water prior to in situ contraction. The mTORC1‐S6K1 and AMPK signalling axes were coactivated immediately post‐contraction, despite potent AMPK‐dependent Ser792 phosphorylation on the mTORC1 subunit raptor. KD‐AMPK muscles displayed normal mTORC1‐S6K1 activation at 0 h and 4 h post‐exercise, although there was impaired contraction‐stimulated protein synthesis 4 h post‐contraction. Pharmacological/dietary elevation of muscle glycogen content augmented contraction‐stimulated mTORC1‐S6K1‐S6 signalling and rescued the reduced protein synthesis‐response in KD‐AMPK to wild‐type levels. mTORC‐S6K1 signalling is not influenced by α2‐AMPK during or after intense muscle contraction. Elevated glycogen augments mTORC1‐S6K1 signalling. α2‐AMPK‐deficient KD‐AMPK mice display impaired contraction‐induced muscle protein synthesis, which can be rescued by normalizing muscle glycogen content.

KW - Faculty of Science

KW - AMPK

KW - Glycogen

KW - mTORC1

KW - Protein synthesis

KW - Resistance exercise

KW - Skeletal muscle

U2 - 10.1113/JP279780

DO - 10.1113/JP279780

M3 - Journal article

C2 - 32372406

VL - 598

SP - 2637

EP - 2649

JO - The Journal of Physiology

JF - The Journal of Physiology

SN - 0022-3751

IS - 13

ER -