The role of mTOR signaling in the regulation of protein synthesis and muscle mass during immobilization in mice

Abstract

The maintenance of skeletal muscle mass contributes substantially to health and to issues associated with the quality of life. It has been well recognized that skeletal muscle mass is regulated by mechanically induced changes in protein synthesis, and that signaling by mTOR is necessary for an increase in protein synthesis and the hypertrophy that occurs in response to increased mechanical loading. However, the role of mTOR signaling in the regulation of protein synthesis and muscle mass during decreased mechanical loading remains largely undefined. In order to define the role of mTOR signaling, we employed a mouse model of hindlimb immobilization along with pharmacological, mechanical and genetic means to modulate mTOR signaling. The results first showed that immobilization induced a decrease in the global rates of protein synthesis and muscle mass. Interestingly, immobilization also induced an increase in mTOR signaling, eIF4F complex formation and cap-dependent translation. Blocking mTOR signaling during immobilization with rapamycin not only impaired the increase in eIF4F complex formation, but also augmented the decreases in global protein synthesis and muscle mass. On the other hand, stimulating immobilized muscles with isometric contractions enhanced mTOR signaling and rescued the immobilization-induced decrease in global protein synthesis through a rapamycin-sensitive mechanism that was independent of ribosome biogenesis. Unexpectedly, the effects of isometric contractions were also independent of eIF4F complex formation. Similar to isometric contractions, overexpression of Rheb in immobilized muscles enhanced mTOR signaling, cap-dependent translation and global protein synthesis, and prevented the reduction in fiber size. Therefore, we conclude that the activation of mTOR signaling is both necessary and sufficient to alleviate the decreases in protein synthesis and muscle mass that occur during immobilization. Furthermore, these results indicate that the activation of mTOR signaling is a viable target for therapies that are aimed at preventing muscle atrophy during periods of mechanical unloading.

Key Markers of mTORC1-Dependent and mTORC1-Independent Signaling Pathways Regulating Protein Synthesis in Rat Soleus Muscle During Early Stages of Hindlimb Unloading

“…In these studies, using radioactive methods, Loughna et al estimated the fractional rate of protein synthesis [7], and Fluckey et al assessed the rate of protein synthesis in vitro [8,9]. The use of in vivo SUnSET technique, which was applied in our study, has shown a decrease in the protein synthesis rate in soleus muscle of mice after 7 days of hindlimb immobilization [32]. The general interest of our study was to identify the possible intracellular mechanisms/ pathways that could be implicated in a decline in protein synthesis rate in rat soleus by the 3 rd day of hindlimb unloading.…”

From physical inactivity to immobilization: Dissecting the role of oxidative stress in skeletal muscle insulin resistance and atrophy

“…Indeed, numerous studies demonstrated that a reduction in muscle protein fractional synthesis rate (FSR) occurs in the first days of immobilization [53,75,76]. This rapid reduction of protein synthesis persists for several weeks since a decrease of muscle FSR has been also reported in human skeletal muscle after 14 and 28 days of bed rest [77,78].…”

“…Interestingly, skeletal muscle exhibits alteration in PI3K/Akt/mTORC1 axis during immobilization [75,76,[80][81][82]. This phenomenon, called anabolic resistance, emphasizes the reduced response to anabolic stimuli [80,82].…”

Síntese proteica em suínos: como fêmeas, machos não castrados e castrados respondem a este processo?

“…Além da metionina, ocorre a participação de uma proteína conhecida como mTOR (mammalian target of rapamycin), considerada um fator chave da síntese proteica no músculo esquelético, por regular numerosos componentes envolvidos na síntese proteica, incluindo fatores de iniciação e elongação (Wang & Proud, 2006, You et al, 2015. Essa proteína quinase exerce um papel fundamental na regulação do crescimento muscular, e vários estudos evidenciaram a importância da mTOR como mediador central do metabolismo e crescimento (Yang et al, 2008).…”

“…Na fase de alongamento, o polipeptídeo formado é alongado pela adição de unidades sucessivas de AA ligadas covalentemente, oriundas da ligação entre o códon do mRNA e o anticódon do tRNA (Rudorf & Lipowsky, 2015). Este processo requer fatores de alongamento, regulados pela mTOR (Wang & Proud, 2006, You et al, 2015 e hidrólise de GTP.…”