Resistance exercise initiates mechanistic target of rapamycin (mTOR) translocation and protein complex co-localisation in human skeletal muscle

Song, Zhe; Moore, Daniel R.; Hodson, Nathan; Ward, Carl; Dent, Jessica R.; O’Leary, Mary F.; Shaw, Andrew M.; Hamilton, D. Lee; Sarkar, Sovan; Gangloff, Yann-Gaël; Hornberger, Troy A.; Spriet, Lawrence L.; Heigenhauser, George J. F.; Philp, Andrew

doi:10.1038/s41598-017-05483-x

Cited by 93 publications

(152 citation statements)

References 49 publications

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“…Recently, however, Korolchuk et al (15) reported that the cellular localisation of these mTOR/lysosomal complexes play a pivotal role in mTOR activation. In support of this hypothesis, we recently reported that a single bout of resistance exercise initiated mTOR/lysosome translocation to the cell periphery, and occurred in parallel to an increase in mTOR activity and interaction between mTOR and proteins involved in translation initiation (23).…”

Section: Introductionmentioning

confidence: 69%

Differential localization and anabolic responsiveness of mTOR complexes in human skeletal muscle in response to feeding and exercise

Hodson

McGlory

Oikawa

et al. 2017

American Journal of Physiology-Cell Physiology

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Mechanistic target of rapamycin (mTOR) resides as two complexes within skeletal muscle. mTOR complex 1 [mTORC1-regulatory associated protein of mTOR (Raptor) positive] regulates skeletal muscle growth, whereas mTORC2 [rapamycin-insensitive companion of mTOR (Rictor) positive] regulates insulin sensitivity. To examine the regulation of these complexes in human skeletal muscle, we utilized immunohistochemical analysis to study the localization of mTOR complexes before and following protein-carbohydrate feeding (FED) and resistance exercise plus protein-carbohydrate feeding (EXFED) in a unilateral exercise model. In basal samples, mTOR and the lysosomal marker lysosomal associated membrane protein 2 (LAMP2) were highly colocalized and remained so throughout. In the FED and EXFED states, mTOR/LAMP2 complexes were redistributed to the cell periphery [wheat germ agglutinin (WGA)-positive staining] (time effect; = 0.025), with 39% (FED) and 26% (EXFED) increases in mTOR/WGA association observed 1 h post-feeding/exercise. mTOR/WGA colocalization continued to increase in EXFED at 3 h (48% above baseline) whereas colocalization decreased in FED (21% above baseline). A significant effect of condition ( = 0.05) was noted suggesting mTOR/WGA colocalization was greater during EXFED. This pattern was replicated in Raptor/WGA association, where a significant difference between EXFED and FED was noted at 3 h post-exercise/feeding ( = 0.014). Rictor/WGA colocalization remained unaltered throughout the trial. Alterations in mTORC1 cellular location coincided with elevated S6K1 kinase activity, which rose to a greater extent in EXFED compared with FED at 1 h post-exercise/feeding ( < 0.001), and only remained elevated in EXFED at the 3 h time point ( = 0.037). Collectively these data suggest that mTORC1 redistribution within the cell is a fundamental response to resistance exercise and feeding, whereas mTORC2 is predominantly situated at the sarcolemma and does not alter localization.

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Section: Introductionmentioning

confidence: 69%

Differential localization and anabolic responsiveness of mTOR complexes in human skeletal muscle in response to feeding and exercise

Hodson

McGlory

Oikawa

et al. 2017

American Journal of Physiology-Cell Physiology

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“…As a nodal sensor and integrator of environmental cues for organismal growth and homeostasis, the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) is particularly relevant since an acute muscle contraction increases phosphorylation of mTOR at Ser‐2448, downstream p70S6 kinase‐1 (S6K1) at Thr‐389 and rpS6 at Ser‐240/244 along with increased protein synthesis . Importantly, mTORC1, but not mTORC2, is critical for maintaining muscle mass and metabolic function, and activation of mTORC1 contributes significantly to increased protein synthesis and hypertrophy induced by resistance exercise . We speculated that resistance training induces both catabolic and metabolic adaptations in skeletal muscle through mTORC1 pathway for the following reasons: (i) Both mTOR‐dependent and ‐independent mechanisms contribute to increased protein synthesis and muscle hypertrophy induced by resistance exercise‐mimicking contractions; (ii) mTORC1 in skeletal muscle is required for normal insulin sensitivity and intramyocellular lipid content, and (iii) Isometric contractions increase Akt phosphorylation and Glut4 translocation to plasma membrane .…”

Section: Discussionmentioning

confidence: 99%

A novel voluntary weightlifting model in mice promotes muscle adaptation and insulin sensitivity with simultaneous enhancement of autophagy and mTOR pathway

et al. 2020

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Our understanding of the molecular mechanisms underlying adaptations to resistance exercise remains elusive despite the significant biological and clinical relevance. We developed a novel voluntary mouse weightlifting model, which elicits squat‐like activities against adjustable load during feeding, to investigate the resistance exercise‐induced contractile and metabolic adaptations. RNAseq analysis revealed that a single bout of weightlifting induced significant transcriptome responses of genes that function in posttranslational modification, metabolism, and muscle differentiation in recruited skeletal muscles, which were confirmed by increased expression of fibroblast growth factor‐inducible 14 (Fn14), Down syndrome critical region 1 (Dscr1) and Nuclear receptor subfamily 4, group A, member 3 (Nr4a3) genes. Long‐term (8 weeks) voluntary weightlifting training resulted in significantly increases of muscle mass, protein synthesis (puromycin incorporation in SUnSET assay) and mTOR pathway protein expression (raptor, 4e‐bp‐1, and p70S6K proteins) along with enhanced muscle power (specific torque and contraction speed), but not endurance capacity, mitochondrial biogenesis, and fiber type transformation. Importantly, weightlifting training profound improved whole‐body glucose clearance and skeletal muscle insulin sensitivity along with enhanced autophagy (increased LC3 and LC3‐II/I ratio, and decreased p62/Sqstm1). These data suggest that resistance training in mice promotes muscle adaptation and insulin sensitivity with simultaneous enhancement of autophagy and mTOR pathway.

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“…Recent work from our lab (11, 28), and others (15) suggests that mTORC1 activation in skeletal muscle involves the translocation of mTORC1-lysosome complexes to peripheral regions of the cell (12). Here, we report a similar process by which mTOR-LAMP2 co-localize in the fasted state, prior to mTOR-LAMP2 complex translocation post PRO-CHO ingestion.…”

Section: Discussionmentioning

confidence: 99%

“…Immunohistochemical analysis was conducted as described previously (28). In short, 5µm sections of muscle tissue were sectioned at -25°C using a Bright 5040 Cryostat (Bright Instrument Company Ltd., Huntingdon, UK) and transferred to room temperature (RT) glass slides (VWR international, UK) and allowed to airdry for ∼1h.…”

Section: Methodsmentioning

confidence: 99%

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Protein-carbohydrate ingestion alters Vps34 cellular localization independent of changes in kinase activity in human skeletal muscle

Hodson

Dent

Song

et al. 2020

Preprint

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The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) regulates cell size and growth in response to nutrients, however, the mechanisms by which nutrient levels are sensed by mTORC1 in human skeletal muscle are yet to be fully elucidated. The Class III PI3Kinase Vps34 has recently been proposed as a sensor essential for mTORC1 activation following nutrient stimulation. We therefore investigated the effects of increasing nutrient availability through protein-carbohydrate (PRO-CHO) feeding on Vps34 kinase activity and cellular localization in human skeletal muscle. Eight young, healthy males (age – 21 ± 0.5yrs, mean ± SEM) ingested a PRO-CHO beverage containing 20/44/1g PRO/CHO/FAT respectively, with skeletal muscle biopsies obtained at baseline and 1h and 3h post-feeding. PRO-CHO feeding did not alter Vps34 kinase activity, but did stimulate Vps34 translocation toward the cell periphery (PRE (mean±SEM) - 0.273±0.021, 1h - 0.347±0.022, Pearson’s Coefficient (r)) where it co-localized with mTOR (PRE – 0.312±0.018, 1h – 0.348±0.024, Pearson’s Coefficient (r))). These alterations occurred in parallel to an increase in S6K1 kinase activity – 941±164% of PRE at 1h post-feeding). Subsequent in vitro experiments in C2C12 and human primary myotubes displayed no effect of the Vps34-specific inhibitor SAR405 on mTORC1 signalling responses to elevated nutrient availability. Therefore, in summary, PRO-CHO ingestion does not increase Vps34 activity in human skeletal muscle, whilst pharmacological inhibition of Vps34 does not prevent nutrient stimulation of mTORC1 in vitro. However, PRO-CHO ingestion promotes Vps34 translocation to the cell periphery, enabling Vps34 to associate with mTOR. Therefore, our data suggests that interaction between Vps34 and mTOR, rather than changes in Vps34 activity per se may be involved in PRO-CHO activation of mTORC1 in human skeletal muscle.

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Resistance exercise initiates mechanistic target of rapamycin (mTOR) translocation and protein complex co-localisation in human skeletal muscle

Cited by 93 publications

References 49 publications

Differential localization and anabolic responsiveness of mTOR complexes in human skeletal muscle in response to feeding and exercise

Differential localization and anabolic responsiveness of mTOR complexes in human skeletal muscle in response to feeding and exercise

A novel voluntary weightlifting model in mice promotes muscle adaptation and insulin sensitivity with simultaneous enhancement of autophagy and mTOR pathway

Protein-carbohydrate ingestion alters Vps34 cellular localization independent of changes in kinase activity in human skeletal muscle

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