Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo

Bodine, Sue C.; Stitt, Trevor N.; Gonzàlez, Michael; Kline, William O.; Stover, Gretchen L.; Bauerlein, Roy; Zlotchenko, Elizabeth; Scrimgeour, Angus G.; Lawrence, John C.; Glass, David J.; Yancopouloš, George D.

doi:10.1038/ncb1101-1014

Cited by 2,242 publications

(2,338 citation statements)

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“…Rapamycin also completely blunted leucine associated myotube growth, similar to previous findings in rodents following compensatory hypertrophy (Bodine et al, 2001), suggesting that the impact on muscle force was at least partially due to lack of muscle growth.…”

Section: Discussionsupporting

confidence: 88%

Leucine elicits myotube hypertrophy and enhances maximal contractile force in tissue engineered skeletal muscle in vitro

Martin

Turner

Farrington

et al. 2017

Journal Cellular Physiology

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The amino acid leucine is thought to be important for skeletal muscle growth by virtue of its ability to acutely activate mTORC1 and enhance muscle protein synthesis, yet little data exist regarding its impact on skeletal muscle size and its ability to produce force. We utilized a tissue engineering approach in order to test whether supplementing culture medium with leucine could enhance mTORC1 signaling, myotube growth, and muscle function. Phosphorylation of the mTORC1 target proteins 4EBP‐1 and rpS6 and myotube hypertrophy appeared to occur in a dose dependent manner, with 5 and 20 mM of leucine inducing similar effects, which were greater than those seen with 1 mM. Maximal contractile force was also elevated with leucine supplementation; however, although this did not appear to be enhanced with increasing leucine doses, this effect was completely ablated by co‐incubation with the mTOR inhibitor rapamycin, showing that the augmented force production in the presence of leucine was mTOR sensitive. Finally, by using electrical stimulation to induce chronic (24 hr) contraction of engineered skeletal muscle constructs, we were able to show that the effects of leucine and muscle contraction are additive, since the two stimuli had cumulative effects on maximal contractile force production. These results extend our current knowledge of the efficacy of leucine as an anabolic nutritional aid showing for the first time that leucine supplementation may augment skeletal muscle functional capacity, and furthermore validates the use of engineered skeletal muscle for highly‐controlled investigations into nutritional regulation of muscle physiology.

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Section: Discussionsupporting

confidence: 88%

Leucine elicits myotube hypertrophy and enhances maximal contractile force in tissue engineered skeletal muscle in vitro

Martin

Turner

Farrington

et al. 2017

Journal Cellular Physiology

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“…mTORC1 is well defined as essential to loading induced muscle growth in rodents [89] and stimulus induced increases in MPS in humans [90,91]. Activation of mTORC1 is required for increases in protein synthesis with amino acids [90] and resistance exercise [91].…”

Section: The Molecular Regulation Of Resistance Training Adaptationmentioning

confidence: 99%

“…Activation of mTORC1 is required for increases in protein synthesis with amino acids [90] and resistance exercise [91]. When mTORC1 activity [89] or the activity of its down stream target p70S6K1 [92,93] are impaired then muscle mass is impinged. It therefore is logical to assume that increases in muscle protein synthesis could be enhanced by enhancing the activation of mTORC1.…”

Section: The Molecular Regulation Of Resistance Training Adaptationmentioning

confidence: 99%

“…However, when insulin is infused to supra-physiological levels mTORC1 is potently activated without a concomitant increase in muscle protein synthesis [99]. So while the data are clear that mTORC1 is required for load-induced growth [89], resistance exercise [91] and feeding [90], it is still very unclear if manipulating mTORC1 above what occurs physiologically will lead to enhanced muscle growth.…”

Section: The Molecular Regulation Of Resistance Training Adaptationmentioning

confidence: 99%

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New strategies in sport nutrition to increase exercise performance

Hamilton

Philp

et al. 2016

Free Radical Biology and Medicine

169

118

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Despite over 50 years of research, the field of sports nutrition continues to grow at a rapid rate. Whilst the traditional research focus was one that centred on strategies to maximize competition performance, emerging data in the last decade has demonstrated how both macronutrient and micronutrient availability can play a prominent role in regulating those cell signalling pathways that modulate skeletal muscle adaptations to endurance and resistance training. Nonetheless, in the context of exercise performance, it is clear that carbohydrate (but not fat) still remains king and that carefully chosen ergogenic aids (e.g. caffeine, creatine, sodium bicarbonate, beta-alanine, nitrates) can all promote performance in the correct exercise setting. In relation to exercise training, however, it is now thought that strategic periods of reduced carbohydrate and elevated dietary protein intake may enhance training adaptations whereas high carbohydrate availability and antioxidant supplementation may actually attenuate training adaptation. Emerging evidence also suggests that vitamin D may play a regulatory role in muscle regeneration and subsequent hypertrophy following damaging forms of exercise. Finally, novel compounds (albeit largely examined in rodent models) such as epicatechins, nicotinamide riboside, resveratrol, β-hydroxy β-methylbutyrate, phosphatidic acid and ursolic acid may also promote or attenuate skeletal muscle adaptations to endurance and strength training. When taken together, it is clear that sports nutrition is very much at the heart of the Olympic motto, Citius, Altius, Fortius (faster, higher, stronger).

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“…It is known that IGF‐1 has a key role both in muscle and nerve tissue anabolism and consequently locally enhances muscle and promotes neuronal survival 35, 36, 37. The IGF‐1 gene, which encodes IGF‐1 undergoes alternative splicing producing multiple isoforms.…”

Section: Discussionmentioning

confidence: 99%

αCAR IGF‐1 vector targeting of motor neurons ameliorates disease progression in ALS mice

Eleftheriadou

Manolaras

Irvine

et al. 2016

Ann Clin Transl Neurol

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ObjectiveWe have previously described the generation of coxsackievirus and adenovirus receptor (α CAR)‐targeted vector, and shown that intramuscular delivery in mouse leg muscles resulted in specific retrograde transduction of lumbar‐motor neurons (MNs). Here, we utilized the α CAR‐targeted vector to investigate the in vivo neuroprotective effects of lentivirally expressed IGF‐1 for inducing neuronal survival and ameliorating the neuropathology and behavioral phenotypes of the SOD1G93A mouse model of ALS.MethodsWe produced cell factories of IGF‐1 expressing lentiviral vectors (LVs) bearing α CAR or Vesicular Stomatitis Virus glycoprotein (VSV‐G) on their surface so as to compare neuroprotection from MN transduced versus muscle transduced cells. We performed intramuscular delivery of either α CAR IGF‐1 or VSVG IGF‐1 LVs into key muscles of SOD1G93A mice prior to disease onset at day 28. Motor performance, coordination and gait analysis were assessed weekly.ResultsWe observed substantial therapeutic efficacy only with the α CAR IGF‐1 LV pretreatment with up to 50% extension of survival compared to controls. α CAR IGF‐1 LV‐treated animals retained muscle tone and had better motor performance during their prolonged survival. Histological analysis of spinal cord samples at end‐stage further confirmed that α CAR IGF‐1 LV treatment delays disease onset by increasing MN survival compared with age‐matched controls. Intrastriatal injection of α CAR eGFP LV in rats leads to transduction of neurons and glia locally and neurons in olfactory bulb distally.InterpretationOur data are indicative of the efficacy of the α CAR IGF‐1 LV in this model and support its candidacy for early noninvasive neuroprotective therapy in ALS.

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Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo

Cited by 2,242 publications

References 37 publications

Leucine elicits myotube hypertrophy and enhances maximal contractile force in tissue engineered skeletal muscle in vitro

Leucine elicits myotube hypertrophy and enhances maximal contractile force in tissue engineered skeletal muscle in vitro

New strategies in sport nutrition to increase exercise performance

αCAR IGF‐1 vector targeting of motor neurons ameliorates disease progression in ALS mice

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