The Molecular Basis for Load-Induced Skeletal Muscle Hypertrophy

Abstract

In a mature (weight neutral) animal, an increase in muscle mass only occurs when the muscle is loaded sufficiently to cause an increase in myofibrillar protein balance. A tight relationship between muscle hypertrophy, acute increases in protein balance, and the activity of the mechanistic target of rapamycin complex 1 (mTORC1) was demonstrated 15 years ago. Since then, our understanding of the signals that regulate load-induced hypertrophy has evolved considerably. For example, we now know that mechanical load activates mTORC1 in the same way as growth factors, by moving TSC2 (a primary inhibitor of mTORC1) away from its target (the mTORC activator) Rheb. However, the kinase that phosphorylates and moves TSC2 is different in the two processes. Similarly, we have learned that a distinct pathway exists whereby amino acids activate mTORC1 by moving it to Rheb. While mTORC1 remains at the forefront of load-induced hypertrophy, the importance of other pathways that regulate muscle mass are becoming clearer. Myostatin, is best known for its control of developmental muscle size. However, new mechanisms to explain how loading regulates this process are suggesting that it could play an important role in hypertrophic muscle growth as well. Lastly, new mechanisms are highlighted for how β2 receptor agonists could be involved in load-induced muscle growth and why these agents are being developed as non-exercise-based therapies for muscle atrophy. Overall, the results highlight how studying the mechanism of load-induced skeletal muscle mass is leading the development of pharmaceutical interventions to promote muscle growth in those unwilling or unable to perform resistance exercise.

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

“…Since, muscle loading (e.g., resistance exercise) and amino acids can stimulate mTORC1 and protein synthesis through diverse mechanisms (Marcotte et al, 2015), and as such implement an additive effect on muscle growth, we conducted a final set of experiments to determine if this effect could be modelled in vitro, and whether the two stimuli would act together to increase maximal muscle force production. It was found that both leucine and electrical stimulation alone resulted in an approximately 60% increase in maximal force production, while combining the two stimuli resulted in an approximately 110% increase in contractile force compared to control muscles.…”

“…mTORC1 signaling has consistently shown to be activated in response to both muscle loading (e.g., resistance exercise), and amino acid consumption/treatment (Marcotte, West, & Baar, 2015), and as such these stimuli represent excellent candidates as therapies for attenuating the muscle wasting associated with a number of disease states and ageing. Indeed, acute human studies have observed activation of mTORC1 and its downstream targets (e.g., p70S6K, rpS6, and 4EBP‐1) following ingestion of mixed amino acids, and this is coupled with an increase in muscle protein synthesis (MPS) in the ensuing 60–120 min (Atherton, Etheridge et al, 2010; Koopman et al, 2006; Paddon‐Jones et al, 2004; Volpi, Kobayashi, Sheffield‐Moore, Mittendorfer, & Wolfe, 2003).…”

Glucocorticoids and Skeletal Muscle

“…Downstream of PI3K/Akt is the serine-threonine kinase, mTOR, which is a major regulator of skeletal muscle size [ 40 ]. As previously noted, mTORC1 activity, as measured by the phosphorylation of S6K1 and 4E-BP1, is suppressed in response to glucocorticoid treatment.…”

Protein supplementation does not alter intramuscular anabolic signaling or endocrine response after resistance exercise in trained men

“…Since the end result of both resistance exercise and growth factors is the movement of TSC2 away from Rheb via different upstream kinases, resistance exercise and transient exercise-induced elevations in circulating hormones may not offer an additive effect [13][14][15][16]. However, amino acids (e.g., leucine) promote mTORC1 in a parallel fashion, independent of TSC2, allowing for a synergistic effect of amino acid ingestion on muscle protein A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 5 synthesis following resistance exercise [7,17]. Several mediators of amino acid signaling have been identified to lie upstream of mTORC1 [18].…”

“…While several upstream mediators have been identified to initiate mTORC1 signaling through distinct mechanisms, they appear to converge on increasing the activity of Rheb (Ras homolog enriched in brain) [7].TSC2 (tumor sclerosis complex 2) negativelyregulates the GTPloading state of Rheb, and upon phosphorylation, TSC2 is sequestered away from Rheb allowing mTORC1 to be activated [7,8]. Resistance exercise and growth factors including insulin and insulin-like growth factor-1 (IGF-1)lead to the phosphorylation of TSC2 [9][10][11].…”