Resistance training causes muscle hypertrophic remodeling, primarily through mammalian target of rapamycin (mTOR)-mediated protein synthesis (1). Endurance training upregulates adenosine monophosphate-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), enhancing mitochondrial biogenesis in skeletal muscle (2). Previous in vitro studies proposed antagonistic crosstalk between mTOR and PGC-1α pathways, wherein their signaling axes compete for transcriptional/translational resources in certain cell types (3). For example, AMPK inhibits mTOR, relieving its suppression of mitophagy in skeletal muscle (4). However, a study found that resistance training increased skeletal muscle PGC-1α and mTOR activities in healthy young men, suggesting that the interfering effects might not exist in vivo (5). Moreover, a research has demonstrated that mTOR not only exerts its traditional function of driving muscle hypertrophy, but also indirectly promotes muscle PGC-1α signaling in mice (6). Thus, integrative adaptations of skeletal muscle mediated by mTOR are not just confined to controlling muscular growth. mTOR also influences mitochondrial biogenesis signaling. Drugs or exercises targeting the mTOR may yield treatment strategies for the chronic diseases such as diabetes and sarcopenia. Present article mainly discussed the regulation of mitochondrial biogenesis by mTOR in skeletal muscle.

mTOR positively regulates protein synthesis and ribosomes biogenesis, contributing to the skeletal muscle hypertrophic response (7). The skeletal muscle hypertrophic adaptation is meditated by both mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC1 is the primary kinase responsible for controlling muscle hypertrophy with mechanical loads (7). For example, genetic deleting tuberous sclerosis complex (TSC, a mTORC1 inhibitor) promoted the mTORC1 signaling, and hypertrophic adaptation and atrophy-resistance of skeletal muscle also occurred after denervation operation in mice (8). The muscle hypertrophic response is mediated by the regulatory-associated protein of mTOR (Raptor) which is an essential part of mTORC1. After mechanical overload, muscle Raptor-deletion mice exhibited blunted mTORC1 signaling and attenuated muscle mass accrual (8). Muscle hypertrophy and protein synthesis were accelerated when mTORC1 was activated by the upstreaming regulator protein kinase B (Akt), whereas rapamycin-inhibited mTORC1 blunted mechanical overload-induced hypertrophy in mice (9, 10).

After activation by resistance exercise or/and amino acid ingestion, mTORC1 can localize with lysosomes and move toward the cell membrane, enhancing protein translation and accretion in skeletal muscle (11). Resistance exercise acutely increased mTORC1 activity and mTOR-lysosome translocation of II fibers 3 h post-exercise in young men (12). Exercise combined with feeding may result in synergistic effect because resistance training plus protein-carbohydrate feeding increased muscle mTORC1 signaling greater than exercise alone in young men (13). Eight weeks of resistance training further enhanced the Akt/mTORC1 phosphorylation in skeletal muscle, driving muscle hypertrophy in men (14). Therefore, mTORC1 is an essential regulator of the muscle hypertrophic adaptation by resistance training. A study found mTORC2 also positively regulates the muscle hypertrophic change with muscle contraction because the reduced extent of protein synthesis and hypertrophic response under the inhibition of both mTORC1 and mTORC2 was higher than that under the single inhibition of mTORC1 (15). However, the precise mechanism of mTORC2-mediated muscle hypertrophy with muscle contraction is unclear.

A key downstream protein of mTORC1 is ribosomal S6 protein kinase 1 (S6K1), which promotes the functions of eukaryotic translation initiation factor 4B, eukaryotic elongation factor 2, and ribosomal protein S6, accelerating protein synthesis and the hypertrophic alteration in skeletal muscle (7). Either high load resistance training or low load resistance training with more fatigue, increased S6K1 phosphorylation and mTORC1-associated signals of skeletal muscle in humans during recovery period, which meant S6K1 is implicated in the skeletal muscle hypertrophic response to mechanical overload (16). Eukaryotic initiation factor 4E binding proteins (4E-BPs) are another downstream target of mTORC1. Once phosphorylated by mTORC1, 4E-BPs dissociate from eukaryotic translation initiation factor 4E (eIF4E), enabling eIF4F formation, which then increases the ribosomal biogenesis contributing to the skeletal muscle hypertrophy (7).

Upstream regulators of mTORC1 involved in muscle hypertrophic remodeling include insulin-like growth factor-1 (IGF-1), extracellular signal regulated kinase (ERK), peroxisome proliferator-activated receptor γ coactivator 1α4 (PGC-1α4), and diacylglycerol kinase ζ (DGKζ) (7). These regulators modulate mTORC1 in an independent manner. Most growth factors that stimulate mTORC1 are blocked by TSC. IGF-1 is a classic regulator for protein synthesis in skeletal muscle. Following feeding or mechanical load stresses, IGF-1 binds to IGF-1 receptor and phosphorylates an intracellular adaptor protein insulin receptor substrate-1, which phosphorylates phosphoinositide 3-kinase (PI3K) followed by Akt activation. Akt inhibits tuberous TSC, resulting in activation of small G protein Ras homolog enriched in brain (Rheb), which then activates mTORC1 in skeletal muscle (17). ERK also inhibits TSC to initiate the skeletal muscle mTORC1 activation in the beginning of mechanical overload stresses independently of IGF-1 signaling (18). DGKζ converts diacylglycerol into phosphatidic acid, which binds to the FKBP12-rapamycin binding domain of mTORC1 and enhances mTORC1 activity, which is critical for the skeletal muscle hypertrophic response to mechanical overloads (19). PGC-1α4 differs from other family members of PGC-1α in that resistance training preferentially initiates PGC-1α4 transcriptional expression, which then leads to mTORC1-mediated muscle hypertrophic signaling (20).

In skeletal muscle, emerging evidence demonstrated the competition between mTOR and PGC-1α signals may not exist in vivo. In nutritional supplement or exercises, mTOR may control the PGC-1α pathway via YY1, 4E-BPs, Raptor, and other unknown ways. mTOR coordinates mitochondrial dynamics (fusion/fission balance) and ROS homeostasis, potentially modulating mitochondrial biogenesis.

In future, it is urgent to study the interaction between muscle mTOR and PGC-1α, as well as how mTOR influences PGC-1α in exercise and nutrients interventions. mTOR should not be considered as a kinase that is only for cell growth. In resistance training condition, activation of mTOR pathway needs the coordination with PGC-1α-meditated mitochondrial biogenesis because protein synthesis requires more ATP supply. Thus, investigation on the role of mTOR in muscle mitochondrial biogenesis is essential for adjusting exercise and nutritional methods to maximize aerobic capacity for sarcopenia patients. For instance, we can construct combined resistance and endurance trainings. The resistance training session may benefit the non-mTOR protein synthesis pathways and the endurance training session restores the normal function of mTOR by AMPK's inhibitory effect. A meta-analysis demonstrated that resistance combined with endurance exercise elicited significant improvements in sarcopenia-related parameters (36). However, current researches on exercise interventions for sarcopenia still lacks investigation into skeletal muscle mTOR signaling. Future studies are anticipated to validate whether multicomponent exercise can more effectively modulate mTOR signaling dysfunction in animal models. mTOR exerts function in mediating glucose metabolism and insulin signaling. Investigation the effect of mTOR on the mitochondrial function in muscle can support the strategies for understanding of the mechanism of exercise treatment on the diabetes and other chronic diseases.