Effect of mechanistic/mammalian target of rapamycin complex 1 on mitochondrial dynamics during skeletal muscle hypertrophy

Abstract

Mechanistic/mammalian target of rapamycin (mTOR) is a central factor of protein synthesis signaling and plays an important role in the resistance training‐induced increase in skeletal muscle mass and subsequent skeletal muscle hypertrophy response. In particular, mTOR complex 1 (mTORC1) promotes protein synthesis in ribosomes by activating the downstream effectors, p70S6K and 4EBP1, in skeletal muscle and is highly sensitive to rapamycin, an mTOR inhibitor. Recently, resistance training has also been shown to affect mitochondrial dynamics, which is coupled with mitochondrial function. In skeletal muscle, mitochondria dynamically change their morphology through repeated fusion and fission, which may be key for controlling the quality of skeletal muscle. However, how the mechanisms of mitochondrial dynamics function during hypertrophy in skeletal muscle remains unclear. The aim of this study was to examine the impact of mTOR inhibition on mitochondrial dynamics during skeletal muscle hypertrophy. Consistent with previous studies, functional overload by synergist (gastrocnemius and soleus) ablation‐induced progressive hypertrophy (increase in protein synthesis and fiber cross‐sectional area) of the plantaris muscle was observed in mice. Moreover, these hypertrophic responses were significantly inhibited by rapamycin administration. Fourteen days of functional overload increased levels of MFN2 and OPA1, which regulate mitochondrial fusion, whereas this enhancement was inhibited by rapamycin administration. Additionally, overload decreased the levels of DRP1, which regulates mitochondrial fission and oxidative phosphorylation, regardless of rapamycin administration. These observations suggest that the relative reduction in mitochondrial function or content is complemented by enhancement of mitochondrial fusion and that this complementary response may be regulated by mTORC1.

Effects of lactate administration on hypertrophy and mTOR signaling activation in mouse skeletal muscle

“…This in vivo model induces compensatory hypertrophy growth of the plantaris muscle through mechanical overload resulting from the surgical removal of the tendons from the synergist muscles (gastrocnemius and soleus), and is very useful as a model to observe exercise-induced muscle hypertrophy and protein synthesis. Consistent with previous reports (Miyazaki et al, 2011;Moriya & Miyazaki, 2018;Shirai, Obara, & Takemasa, 2020;Uemichi et al, 2021), 14 days of mechanical overload induced 25%-50% muscle hypertrophy and enhanced protein synthesis with activated mTOR signaling in mouse skeletal muscle.…”

“…We performed lateral synergist ablation surgeries, as previously described, (Shirai, Obara, & Takemasa, 2020 ; Uemichi et al, 2021 ) under anesthesia with 2.0% isoflurane air inhalation. This in vivo model induces hypertrophy of the plantaris muscle by mechanical overload (OL), through the surgical removal of synergist muscles (gastrocnemius and soleus) and is very useful as a model to observe exercise‐induced muscle hypertrophy and protein synthesis (Moriya & Miyazaki, 2018 ; Uemichi et al, 2021 ). One of the characteristics of the plantaris muscles used in this experiment is that the type IIA or IIB fibers are dominant (Miyazaki et al, 2004 ; Souza et al, 2014 ).…”

“…We performed lateral synergist ablation surgeries, as previously described, (Shirai, Obara, & Takemasa, 2020;Uemichi et al, 2021) under anesthesia with 2.0% isoflurane air inhalation. This in vivo model induces hypertrophy of the plantaris muscle by mechanical overload (OL),…”

Effect of lactate administration on mouse skeletal muscle under calorie restriction

“…Skeletal muscle mass is regulated by the balance of protein synthesis and breakdown. Mammalian/mechanistic target of rapamycin (mTOR) signaling plays an important role in the maintenance of skeletal muscle mass ( Bodine et al, 2001 ; Uemichi et al, 2021 ). It has been demonstrated that this signaling pathway is activated by overload stimuli such as resistance exercise and the intake of amino acids ( Damas et al, 2016 ; Dickinson et al, 2011 ; Shirai et al, 2021 ).…”

Hypertrophy of Rat Skeletal Muscle Is Associated with Increased SIRT1/Akt/mTOR/S6 and Suppressed Sestrin2/SIRT3/FOXO1 Levels

“…According to our suggestion, the increase in the mass of muscle filaments due to overload was not associated with a similar increase in mitochondrial mass, this could lead to this result. Indeed, a recent paper reports that 14 days of functional overload increased the levels of proteins, which regulate mitochondrial fusion and decreased fission controlling proteins, and this could explain the relative reduction in mitochondrial proteins [ 26 ].…”