Contraction‐regulated mTORC1 and protein synthesis: Influence of AMPK and glycogen. (27th May 2020)

• Record Type: Journal Article
• Authors: Knudsen, Jonas R.; Li, Zhencheng; Persson, Kaspar W.; Li, Jingwen; Henriquez‐Olguin, Carlos; Jensen, Thomas E.
• Is Part Of: Journal of physiology. Volume 598:Number 13(2020)
• Page Start: 2637
• Page End: 2649
• Publication Date: 2020-05-27
• Subjects: AMPK -- glycogen -- mTORC1 -- protein synthesis -- resistance exercise -- skeletal muscle; Physiology -- Periodicals; 612.005
• DOI: 10.1113/JP279780
• Languages: English
• ISSNs: 0022-3751

Abstract

Abstract : Key points: AMP‐activated protein kinase (AMPK)‐dependent Raptor Ser792 phosphorylation does not influence mechanistic target of rapamycin complex 1 (mTORC1)‐S6K1 activation by intense muscle contraction. α2 ‐AMPK activity‐deficient mice have lower contraction‐stimulated protein synthesis. Increasing glycogen activates mTORC1‐S6K1. Normalizing muscle glycogen content rescues reduced protein synthesis in AMPK‐deficient mice. Abstract: 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. Key points: AMP‐activated protein kinase (AMPK)‐dependent Raptor Ser792 phosphorylation does not influence mechanistic target of rapamycin complex 1 (mTORC1)‐S6K1 activation by intense muscle contraction. α2 ‐AMPK activity‐deficient mice have lower contraction‐stimulated protein synthesis. Increasing glycogen activates mTORC1‐S6K1. Normalizing muscle glycogen content rescues reduced protein synthesis in AMPK‐deficient mice.