Muscle metabolic alterations induced by genetic ablation of 4E-BP1 and 4E-BP2 in response to diet-induced obesity

Bacquer, Olivier Le; Combe, Kristell; Montaurier, Christophe; Salles, Jérôme; Giraudet, Christophe; Patrac, Véronique; Domingues-Faria, Carla; Guillet, Christelle; Louche, Katie; Boirie‌, Yves; Sonenberg, Nahum; Moro, Cédric; Walrand, Stéphane

doi:10.1002/mnfr.201700128

Cited by 13 publications

(25 citation statements)

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“…In the present study, using EDL muscles, we observed that protein synthesis was increased under basal conditions and after stimulation with a mix of leucine and insulin in 4E‐BP1/2 DKO mice. This result is in line with previous results where global protein synthesis was found to be increased in vitro in 4E‐BP1/2 DKO haematopoietic stem cells and primary fibroblasts . In another study using 4E‐BP1/2 DKO mice, Steiner et al .…”

Section: Discussionsupporting

confidence: 92%

“…In previous studies, it was observed that deletion of 4E‐BP1 and 4E‐BP2 resulted in reduced energy expenditure, whereas energy expenditure is unaltered in the present study. An important difference between these previous studies and the current one is the age of the mice (24 vs. 6 months), and this difference might in part explain the absence of modification of energy expenditure we are observing.…”

Section: Discussionsupporting

confidence: 56%

“…Global metabolomic and complex lipid analysis of WT and 4E-BP1/2 DKO skeletal muscle revealed robust differences in amino acid homeostasis, carbohydrate abundance, and certain aspects of lipid metabolism. In previous studies, it was observed that deletion of 4E-BP1 and 4E-BP2 resulted in reduced energy expenditure, 7,8 whereas energy expenditure is unaltered in the present study. An important difference between these previous studies and the current one is the age of the mice (24 vs. 6 months), and this difference might in part explain the absence of modification of energy expenditure we are observing.…”

Section: Discussionsupporting

confidence: 52%

“…Amongst them, skeletal muscle is the main energy consuming tissue, and aging is associated with a loss of muscle mass, called sarcopenia. In a recent study, we measured muscle mass in 6‐month‐old mice. Total hindlimb skeletal mass was 418 ± 5 and 432 ± 3 mg in WT and 4E‐BP1/2 DKO mice, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…4E‐BP1 knockout (KO) mice display reduced adipose tissue and increased energy expenditure . In contrast, deletion of both 4E‐BP1 and 4E‐BP2 is associated with increased body weight and increased sensitivity to diet‐induced obesity and insulin resistance . Finally, overexpression of 4E‐BP1 is able to protect mice from age‐induced and diet‐induced obesity and insulin resistance .…”

Section: Introductionmentioning

confidence: 99%

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

Bacquer

Combe

Patrac

et al. 2019

J cachexia sarcopenia muscle

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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‐ 14 C]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 < 0.05). Protein synthesis was higher under both basal (+102%, P < 0.05) and stimulated conditions (+65%, P < 0.05) in DKO skeletal muscle. Metabolomic and complex lipid analysis of skeletal muscle revealed robust differences pertaining to amino acid homeostasis, carbohydrate abundance, and certain aspects of lipid metabolism. In particular, levels of most free amino acids were lower within the 4E‐BP1/2 DKO muscle. Interestingly, although glucose levels were unchanged, differences were observed in the isobaric compound maltitol/lactitol (33‐fold increase, P < 0.01) and in several additional carbohydrate compounds. 4E‐BP1/2 depletion also resulted in accumulation of medium‐chain acylcarnitines and a 20% lower C2/C0 acylcarnitine ratio ( P < 0.01) indicative of reduced β‐oxidation. Conclusions Taken together, these findings demonstrate that deletion of 4E‐BPs is associated with perturbed energy metabolism in skeletal muscle and could have beneficial effects on skeletal muscle mass and function in aging mice. They also identify 4E‐BPs as potential targets for the treatment of sarcopenia.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 56%

Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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