An Evidence-Based Narrative Review of Mechanisms of Resistance Exercise-Induced Human Skeletal Muscle Hypertrophy

Changhyun Lim, Everson A Nunes, Brad S Currier, Jonathan C McLeod, Aaron C Q Thomas, Stuart M Phillips, Changhyun Lim, Everson A Nunes, Brad S Currier, Jonathan C McLeod, Aaron C Q Thomas, Stuart M Phillips

Abstract

Skeletal muscle plays a critical role in physical function and metabolic health. Muscle is a highly adaptable tissue that responds to resistance exercise (RE; loading) by hypertrophying, or during muscle disuse, RE mitigates muscle loss. Resistance exercise training (RET)-induced skeletal muscle hypertrophy is a product of external (e.g., RE programming, diet, some supplements) and internal variables (e.g., mechanotransduction, ribosomes, gene expression, satellite cells activity). RE is undeniably the most potent nonpharmacological external variable to stimulate the activation/suppression of internal variables linked to muscular hypertrophy or countering disuse-induced muscle loss. Here, we posit that despite considerable research on the impact of external variables on RET and hypertrophy, internal variables (i.e., inherent skeletal muscle biology) are dominant in regulating the extent of hypertrophy in response to external stimuli. Thus, identifying the key internal skeletal muscle-derived variables that mediate the translation of external RE variables will be pivotal to determining the most effective strategies for skeletal muscle hypertrophy in healthy persons. Such work will aid in enhancing function in clinical populations, slowing functional decline, and promoting physical mobility. We provide up-to-date, evidence-based perspectives of the mechanisms regulating RET-induced skeletal muscle hypertrophy.

Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Sports Medicine.

Figures

FIGURE 1
FIGURE 1
The formulation of external vs internal variables for skeletal muscle hypertrophy. Although external variables (input) are indispensable to activate internal variables for skeletal muscle hypertrophy (output), the response of internal variables stimulated by external variables is the key determinant of skeletal muscle hypertrophy. The size of the color squares reflects the extent of the variables’ contribution to muscle hypertrophy. We are uncertain of the nature of the interaction between the variables and have shown them as multiplicative (•); however, we acknowledge that the function could be additive or more complex (i.e., an unknown function) relationship.
FIGURE 2
FIGURE 2
Overview of mTORC1-related protein synthesis pathways. Multiple signaling cascades converge on mTORC1 and contribute to protein translation. Cytosolic leucine and arginine relieve inhibition on GATOR2 by Sestrin2 and CASTOR1, respectively, and subsequently promote mTORC1-induced protein synthesis via GATOR2–GATOR1–Rag signaling. Mechanical stress causes Cγ1 to colocalize around FAK, catalyzing Ptdlns(4,5)P2 conversion to PA, and subsequently activates the HIPPO pathway (YAP and TAZ). Filamin-C and Bag3 interaction also activates the HIPPO pathway. The HIPPO pathway promotes mTORC1 signaling via the suppression of PTEN. The PI3K–Akt–TSC signaling cascade regulates mTORC1 signaling via Rheb, although Akt can directly promote mTORC1 signaling via PRAS40. AMPK and REDD1 inhibit mTORC1 via TSC; AMPK can also inhibit mTORC1 directly via Raptor. mTORC1 promotes protein synthesis by activating several translational and ribosomal components, and Ras–MEK–ERK 1/2 signaling converges on common factors. 4EBP-1, eukaryotic translation initiation factor 4E-binding protein 1; Akt, protein kinase B; AMPK, AMP-activated protein kinase; Arg, arginine; eEF2, eukaryotic elongation factor 2; eIF4B, eukaryotic translation initiation factor 4B; eIF4E, eukaryotic translation initiation factor 4E; eIF4G, eukaryotic translation initiation factor 4G; ERK 1/2, extracellular signal-related kinase 1/2; FAK, focal adhesion kinase; IGF-1, insulin-like growth factor 1; Leu, leucine; MEK, mitogen-activated protein kinase; MNK1, MAP kinase-interacting kinase 1; mTORC1, mechanistic target of rapamycin complex 1; p70S6K, p70 S6 kinase 1; p90RSK, p90 ribosomal protein S6 kinase; PI3K, phosphoinositide 3-kinase; PRAS40, proline-rich AKT substrate 40 kDa; PtdIns(4,5)P2, phosphatidylinositol 4,5-biphosphate; PTEN, phosphatase and tensin homolog; Raptor, regulatory-associated protein of mTOR; REDD1, regulated in development and DNA damage responses 1; Rheb, Ras homolog enriched in brain; rpS6, ribosomal Protein S6; TAZ, transcriptional coactivator with PDZ-binding motif; TSC, tuberous sclerosis complex; YAP, Yes-associated protein 1.
FIGURE 3
FIGURE 3
A proposed framework of changes in MPS, translational capacity, and muscle fiber CSA in response to RET. The overarching concept is that initial increases in MPS are a biological response to support remodeling of damaged muscle protein and eventually muscle hypertrophy. A, The early-stage increases in MPS are sustained partly by a concomitant elevated translational capacity to support the remodeling of damaged structural and contractile elements of the muscle proteome. B, After the attenuation of exercise-induced muscle damage, there is a reduction in the contribution of MPS to the remodeling of proteins related to the structural and architectural apparatus toward contractile muscle proteins. C, After a relatively short period of time, the rates of MPS are subsequently regulated by the adaptive increase in translational efficiency. D, The result is a detectable increase in skeletal muscle size and mass. All these responses are designed to support an expansion of the muscle protein pool, that is, fiber CSA. The schematic and legend are adapted (with permission) from McGlory et al. (53). A.U., arbitrary units.
FIGURE 4
FIGURE 4
A comparison of the changes in exogenous vs endogenous testosterone in serum. A, Schematic of the circadian changes of serum testosterone throughout 11 d showing the effect of one bout of RE in healthy young men (RE-induced ~30 min testosterone peak; based on data from Willoughby and Taylor [87]). In addition, a representation of the effect of an intramuscular testosterone injection (200 mg testosterone enanthate) vs a schematic of the normal diurnal variation in testosterone concentrations throughout a given week (based on data from Dobs et al. (88)). B, Cumulative AUC of serum testosterone over the first 7 d comparing 1) DV changes, 2) DV + 1 bouts of RE, and 3) 200 mg T enanthate. The schematic is adapted (with permission) from Schroeder et al. (86). AUC, area under the curve; DV, diurnal variation; T, testosterone.
FIGURE 5
FIGURE 5
Representative factors that contribute to the anabolic resistance of skeletal muscle with aging and disease. This schematic is adapted (with permission) from McKendry et al. (2). E, estrogen; T, testosterone.
FIGURE 6
FIGURE 6
Schematic illustration of the mechanisms underpinning skeletal muscle hypertrophy response to RET. After mechanical stimuli, phospholipase Cγ1 colocalizes around FAK and catalyzes the conversion of Ptdlns(4,5)P2 to PA that activates the HIPPO pathway (YAP and TAZ). YAP and TAZ promote the mTOR signaling pathway via the suppression of PTEN, regulate SC activation, and mediate the expression of L-type amino acid transporter 1 (LAT1). Interaction between Filamin-C and Bag3 increases the activation of the HIPPO pathway. Translational capacity and efficacy via ribosome are essential determinants for muscle hypertrophy. Besides increased gene expression during RE, the UTR of mRNA is regulated and closely correlated with muscle growth. The AR content is associated with RET-induced hypertrophy, whereas RE-induced acute changes in serum testosterone show no association with muscle growth. In human trials, RE-induced increased CK and inflammation factors have no effects on muscle hypertrophy. However, RET reduces resting concentration of inflammation cytokines in aging and clinical illness. AR, androgen receptor; ECM, extracellular matrix; FAK, focal adhesion kinase; IκBα, NF-κB inhibitor alpha; IKK, IκB kinase; LAT1, L-type amino acid transporter 1; mTOR, mechanistic target of rapamycin; MuRF 1, muscle RING-finger protein 1; NF-κB, nuclear factor kappa light-chain enhancer of activated B; PGE2, prostaglandin E2; PTEN, phosphatase and tensin homolog; RE, resistance exercise; RET, resistance exercise training; SC, satellite cells; TAZ, transcriptional coactivator with PDZ-binding motif; UTR, untranslated region; YAP, Yes-associated protein 1.

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Source: PubMed

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