4E‐BP1 and 4E‐BP2 double knockout mice are protected from aging‐associated sarcopenia

• Published in: Journal of cachexia, sarcopenia and muscle sarcopenia and muscle, 2019-06, Vol.10 (3), p.696-709
• Main Authors: Le Bacquer, Olivier, Combe, Kristell, Patrac, Véronique, Ingram, Brian, Combaret, Lydie, Dardevet, Dominique, Montaurier, Christophe, Salles, Jérôme, Giraudet, Christophe, Guillet, Christelle, Sonenberg, Nahum, Boirie, Yves, Walrand, Stéphane
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Aging; Aging - metabolism; Amino acids; Amino Acids - metabolism; Anabolism; Animals; Antibodies; Body composition; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Diet; Disease Models, Animal; Energy; Energy Metabolism - genetics; Eukaryotic Initiation Factors - genetics; Eukaryotic Initiation Factors - metabolism; Fatty acids; Food and Nutrition; Growth factors; Homeostasis; Humans; Insulin resistance; Laboratory animals; Life Sciences; Lipid Metabolism - genetics; Lipids; Male; Metabolic disorders; Metabolomics; Mice; Mice, Knockout; mTOR; Muscle, Skeletal - pathology; Musculoskeletal system; Nutrition research; Obesity; Original; Physiology; Protein Biosynthesis - genetics; Protein synthesis; Proteins; Proteolysis; Proteostasis - genetics; Sarcopenia; Sarcopenia - genetics; Sarcopenia - pathology; Sarcopenia - therapy; Signal Transduction - genetics; Skeletal muscle; Studies
• ISSN: 2190-5991; 2190-6009
• DOI: 10.1002/jcsm.12412

Background Sarcopenia is the loss of muscle mass/function that occurs during the aging process. The links between mechanistic target of rapamycin (mTOR) activity and muscle development are largely documented, but the role of its downstream targets in the development of sarcopenia is poorly understood. Eukaryotic initiation factor 4E‐binding proteins (4E‐BPs) are targets of mTOR that repress mRNA translation initiation and are involved in the control of several physiological processes. However, their role in skeletal muscle is still poorly understood. The goal of this study was to assess how loss of 4E‐BP1 and 4E‐BP2 expression impacts skeletal muscle function and homeostasis in aged mice and to characterize the associated metabolic changes by metabolomic and lipidomic profiling. Methods Twenty‐four‐month‐old wild‐type and whole body 4E‐BP1/4E‐BP2 double knockout (DKO) mice were used to measure muscle mass and function. Protein homeostasis was measured ex vivo in extensor digitorum longus by incorporation of l‐[U‐14C]phenylalanine, and metabolomic and lipidomic profiling of skeletal muscle was performed by Metabolon, Inc. Results The 4E‐BP1/2 DKO mice exhibited an increase in muscle mass that was associated with increased grip strength (P