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. Last, 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.

Figure 1

The effect of load on muscle hypertrophy. The increase in muscle mass following 10-weeks resistance exercise in CON, animals that received no stimulation; No Weight, animals that exercised without an external weight to prevent dorsiflexion; and Weight, animals where dorsiflexion was resisted by an external load just less than maximal isometric load. Adapted from [26].

Figure 2

The activation of the mechanistic target of rapamycin complex 1 (mTORC1) by growth factors. Growth factors bind to receptor tyrosine kinases that recruit the insulin receptor substrates (IRS1/2) and this bind PI3K to the membrane. When at the membrane, PI3K converts phosphoinositol (4,5) bisphosphate (the two red circles at the membrane) into phosphoinositol (3,4,5) trisphosphate (the three green circles at the membrane), which is a docking site for akt and its upstream kinase the 3-phosphoinositide dependent protein kinase-1 (PDK1). When akt and PDK1 co-localize at the membrane, PDK1 phosphorylates akt at one site and the membrane-associated mTORC2 phosphorylates a second site; resulting in full activation of akt. Active akt turns on mTORC1 by phosphorylating and removing PRAS40 and TSC2 from mTOR and Rheb, respectively.

Figure 3

The activation of the mechanistic target of rapamycin complex 1 (mTORC1) following resistance exercise and feeding. Lifting a heavy weight to failure stimulates a mechanoreceptor that in turn activates an RxRxxS*/T* kinase that phosphorylates and moves the tublerosclerosis complex (TSC2) away from the lysosome allowing Rheb (Ras homologue enriched in brain) to remain in the guanosine triphosphate (GTP) bound state. Simultaneously, amino acid uptake and intracellular amino acid levels increase. The extra amino acids stimulate the leucyl tRNA synthase (LRS) to act as a GTPase activating protein (GAP) towards RagC/D and GATOR (GAP Activity Towards Rags)2 blocks GATOR1 (the GAP of RagA/B) and the Ragulator GTP loads RagA/B and activates the complex. The active Rag complex then binds to raptor and positions mTOR beside its activator GTP bound Rheb. The resulting elevation of mTORC1 activity drives myofibrillar protein synthesis and eventually leads to an increase in muscle mass and strength. LAT1, L-type amino acid transporter; Rab7, Ras-related protein 7; LAMP2, lysosome-associated membrane protein 2; P, phosphorylation; DEPTOR, DEP domain-containing mTOR-interacting protein; GβL, G-protein beta subunit-like protein; PRAS40, proline-rich Akt substrate of 40 kilodaltons; and RAPTOR, the regulatory-associated protein of mTOR.

Figure 4

The role of Smads in the control of muscle mass. Myostatin and similar members of the TGFβ superfamily can phosphorylate Smad2/3 allowing it to bind to the common mediator Smad4 and move to the nucleus. In the nucleus, Smad2/3 drives transcriptional events that result in the transcription of genes that limit muscle size. Smad2/3 signaling can be competitively inhibited at the level of Smad4 binding by Smad1/5/8. BMP7 and other members of the TGFβ superfamily activate Smad1/5/8 through ALK3 and the BMP receptor. Resistance exercise can also limit Smad2/3 signaling by cleaving and activating Notch. The intracellular domain of Notch then moves to the nucleus and blocks Smad2/3 transcription.