Increased strength is the combined effect of improvements in neural activation, muscle fiber size, and connective tissue stiffness. Therefore, concomitant endurance exercise could decrease adaptations of any/all of these physiological parameters. There does not appear to be a decrease in the neural (learning) adaptation since in the early stages of training, when the neural adaptation is the strongest (4, 6, and 8 weeks), strength is similar between strength and concurrent training groups [1, 2]. However, it is possible that neuromuscular fatigue plays a role in the decrease in force as training continues. At this point, no one has measured the effect of concurrent training on connective tissue stiffness, so we are unsure of the role of this tissue in the impaired strength response. In contrast, as stated above, there is some evidence that muscle hypertrophy is impaired in individuals training for both strength and endurance together compared with those training exclusively with strength exercises, and that this correlates quite well with the impaired strength response [2, 3]. Therefore, the primary effect of endurance exercise seems to be a decrease in resistance exercise-induced muscle hypertrophy.

Over the last 15 years we have begun to understand the molecular events that lead to muscle hypertrophy and increased endurance capacity. These studies have shown that for exercise-induced muscle hypertrophy, the key signaling molecule is the mechanistic or mammalian target of rapamycin (mTOR). mTOR is a serine/threonine protein kinase that exists in two complexes. Both complexes contain the DEP domain-containing mTOR-interacting protein (DEPTOR) and the G-protein beta subunit-like protein (GβL; also known as lsT8). These proteins are negative and positive regulators of mTOR, respectively. Complex 1 (mTORC1) also contains the proline-rich Akt substrate of 40 kDa (PRAS40), an inhibitor of mTORC1 activity and the regulatory-associated protein of mTOR (raptor), which specifies the substrates that are phosphorylated by mTORC1. Raptor identifies the substrates for complex 1 by binding to TOS (TOR signaling) motifs, a five amino-acid sequence, found in proteins such as eukaryotic initiation factor (eIF) 4E binding protein-1 (4E-BP1), the 70-kDa ribosomal protein S6 kinase (S6K1), hypoxia-inducible factor-1 (HIF-1), and PRAS40. In contrast, complex 2 (mTORC2) contains the mammalian stress-activated map kinase-interacting protein 1 (mSIN1), which is important for targeting to membranes, the scaffold protein observed with rictor (PROTOR), and the rapamycin-insensitive companion of mTOR (rictor). Much like raptor in complex 1, rictor identifies the substrates that are phosphorylated by mTOR. However, rictor does not recognize TOS motifs and, as a result, in complex 2 mTOR is directed towards a completely different group of proteins including akt/PKB (protein kinase B), serum- and glucocorticoid-induced protein kinase (SGK), and protein kinase C (PKC). Importantly, the macrolide immunosuppressive antibiotic rapamycin specifically inhibits complex 1, allowing researchers to distinguish between the two complexes.

Following resistance exercise there is a significant and sustained increase in the activity of mTORC1, as determined by an increase in S6K phosphorylation [8] and activity [9]. The first indication that this increase in mTOR activity was important for resistance exercise-induced muscle hypertrophy came from work where we showed that the activity of mTOR 6 h following resistance exercise correlated with the increase in muscle mass following 6 weeks of training [8]. This finding in rats has since been demonstrated in humans [10], suggesting that activation of mTORC1 is key to increasing muscle mass and strength.

In many cells, mTOR is activated by growth factors as a way to stimulate protein synthesis [11]. However, resistance exercise activates mTOR in a growth factor-independent manner [12]. Unlike growth factors that use a receptor tyrosine kinase to signal through phosphoinositide 3-kinase (PI3K) to PKB, resistance exercise activates mTOR without activating PI3K [13]. Instead, resistance exercise activates an unidentified kinase (Fig. 2) that phosphorylates the potent mTOR inhibitor tuberin (TSC2) on RxRxx motifs [14]. When TSC2 is phosphorylated in this manner, it binds to 14-3-3 proteins and is moved away from mTOR and its activator Ras-homolog enriched in brain (Rheb). In this way, Rheb becomes activated and stimulates mTORC1 activity, leading to increased protein synthesis.

Fig. 2 The activation of the mechanistic target of rapamycin complex 1 (mTORC1, mTOR, and raptor complex) following resistance exercise and feeding. Lifting a heavy weight to failure stimulates a mechanoreceptor that in turn activates an RxRxxS*/T* kinase (depicted by ??? at the membrane) that phosphorylates and moves the TSC2 away from the lysosome allowing Rheb to remain in the GTP bound state. Simultaneously, amino acid uptake and intracellular amino acid levels increase. The extra amino acids stimulate the LRS to act as a GAP towards RagC/D and GATOR2 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. DEPTOR DEP (Dishevelled, Egl-10 and Pleckstrin) domain-containing mTOR-interacting protein, GβL G-protein beta subunit-like protein, GAP GTPase activating protein, GATOR GAP Activity Towards Rags, GDP guanosine diphosphate, GTP guanosine triphosphate, LAMP2 lysosome-associated membrane protein 2, LAT1 L-type amino acid transporter, LRS leucyl transfer RNA synthase, mTOR mammalian target of rapamycin, mTORC1 mTOR complex 1 P phosphorylation, PRAS40 proline-rich Akt substrate of 40 kDa, Rab7 Ras-related protein 7, raptor the regulatory-associated protein of mTOR, Rheb Ras homolog enriched in brain, TSC2 tublerosclerosis complex Full size image

Contraction-induced dissociation of TSC2 from the lysosome is not the only thing that occurs following resistance exercise that leads to the prolonged activation of mTOR. In the hours after resistance exercise there is also an increase in the rate of amino acid uptake from the blood into the muscle. Specifically, leucine and glutamine are increased within the working muscle [9, 15]. This increase in leucine within the muscle is likely the result of an increase in the primary leucine transporter (LAT1) messenger RNA (mRNA) [16] and protein [17]. Interestingly, the increase in glutamine can help drive leucine uptake since LAT1 transports glutamine out of the muscle as it transports leucine into the muscle in a process called tertiary active transport [18]. As leucine enters the muscle it acts to trigger protein synthesis largely through its ability to activate mTORC1 [19]. As leucine is taken up, it binds to the leucyl-transfer RNA (tRNA) synthetase (LRS). This not only conjugates leucine to its tRNAs, but the LRS also acts as the first step in the amino acid activation of the mTORC1 [20]. LRS may serve as a GTPase activating protein (GAP) towards the small G-protein (RagD), which in turn is a component of a heterodimer of RagA/B and RagC/D that is important for amino acid sensing. When RagD is bound to guanosine triphosphate (GTP) it forms an inactive complex. LRS catalyzes the hydrolysis of this GTP to guanosine diphosphate (GDP) and RagD then interacts with the Ragulator [21]. At the Ragulator, the Rag heterodimer interacts with GATOR (GAP Activity Towards Rags), an octomeric complex that controls the activity of the Rag proteins [22]. In the presence of amino acids, the Rags are activated and recruit mTORC1 to the lysosome by binding to raptor [23, 24]. As discussed above, the activator of mTOR, Rheb, is also located on the lysosome, so the net effect of leucine is to bring mTOR to its activator.

Together, these data suggest that resistance exercise activates mTORC1 through the activation of an RxRxx-directed kinase that phosphorylates and moves the inhibitor TSC2 away from the lysosome (Fig. 2). At the same time, by regulating LAT1, enhanced amino acid uptake moves mTOR to the lysosome where it can be activated by GTP-bound Rheb. This complex molecular process explains both the load-dependent activation of mTOR (more activation of the RxRxx kinase [14]) and the effects of amino acid consumption (increased movement of mTOR to the lysosome and its activator Rheb [23, 24]) on protein synthesis and, finally, muscle hypertrophy [25, 26].

Even though a molecular mechanism exists for the activation of mTORC1 by resistance exercise and protein feeding, this does not prove that mTORC1 is what is necessary for muscle growth. Evidence that mTORC1 drives load-induced muscle hypertrophy was derived from experiments using rapamycin to specifically inhibit the kinase. In mice, Bodine and colleagues showed that daily injections of rapamycin could inhibit muscle hypertrophy [27], and in humans, Drummond and colleagues showed that rapamycin could block the acute increase in protein synthesis after resistance exercise [28]. These experiments suggested that a rapamycin-sensitive process was required for load-induced muscle growth. The specific role of mTOR was demonstrated by an elegant study from the Hornberger laboratory using mice with a knock-in mutation that made mTOR resistant to treatment with rapamycin [29]. As would be expected, in the wild-type animals rapamycin completely blocked muscle hypertrophy. However, in the mice expressing a rapamycin-resistant mutant of mTOR muscle, hypertrophy occurred normally both in the presence and absence of rapamycin [29]. These data showed conclusively that resistance exercise-induced muscle hypertrophy is completely dependent on mTOR. Therefore, research looking for a molecular mechanism underlying the concurrent training effect has been focused exclusively on ways that endurance exercise could inhibit mTORC1 activity.