Differential response of skeletal muscles to mTORC1 signaling during atrophy and hypertrophy

Abstract

BackgroundSkeletal muscle mass is determined by the balance between protein synthesis and degradation. Mammalian target of rapamycin complex 1 (mTORC1) is a master regulator of protein translation and has been implicated in the control of muscle mass. Inactivation of mTORC1 by skeletal muscle-specific deletion of its obligatory component raptor results in smaller muscles and a lethal dystrophy. Moreover, raptor-deficient muscles are less oxidative through changes in the expression PGC-1α, a critical determinant of mitochondrial biogenesis. These results suggest that activation of mTORC1 might be beneficial to skeletal muscle by providing resistance to muscle atrophy and increasing oxidative function. Here, we tested this hypothesis by deletion of the mTORC1 inhibitor tuberous sclerosis complex (TSC) in muscle fibers.MethodSkeletal muscles of mice with an acute or a permanent deletion of raptor or TSC1 were examined using histological, biochemical and molecular biological methods. Response of the muscles to changes in mechanical load and nerve input was investigated by ablation of synergistic muscles or by denervation .ResultsGenetic deletion or knockdown of raptor, causing inactivation of mTORC1, was sufficient to prevent muscle growth and enhance muscle atrophy. Conversely, short-term activation of mTORC1 by knockdown of TSC induced muscle fiber hypertrophy and atrophy-resistance upon denervation, in both fast tibialis anterior (TA) and slow soleus muscles. Surprisingly, however, sustained activation of mTORC1 by genetic deletion of Tsc1 caused muscle atrophy in all but soleus muscles. In contrast, oxidative capacity was increased in all muscles examined. Consistently, TSC1-deficient soleus muscle was atrophy-resistant whereas TA underwent normal atrophy upon denervation. Moreover, upon overloading, plantaris muscle did not display enhanced hypertrophy compared to controls. Biochemical analysis indicated that the atrophy response of muscles was based on the suppressed phosphorylation of PKB/Akt via feedback inhibition by mTORC1 and subsequent increased expression of the E3 ubiquitin ligases MuRF1 and atrogin-1/MAFbx. In contrast, expression of both E3 ligases was not increased in soleus muscle suggesting the presence of compensatory mechanisms in this muscle.ConclusionsOur study shows that the mTORC1- and the PKB/Akt-FoxO pathways are tightly interconnected and differentially regulated depending on the muscle type. These results indicate that long-term activation of the mTORC1 signaling axis is not a therapeutic option to promote muscle growth because of its strong feedback induction of the E3 ubiquitin ligases involved in protein degradation.

Systematic review of the synergist muscle ablation model for compensatory hypertrophy

“…9 Unilateral vs. bilateral surgery Based on the data analyzed, both unilateral and bilateral synergist ablation lead to an increase in muscle mass, with no statistically significant difference between the two types of surgery. Researchers working with unilateral surgery report a mean increase in muscle mass of 46.8 ± 2.6% 14 days following synergist ablation, 4,12,61,63 whereas those working with bilateral surgery report an increase of 52.3 ± 3.1% in the same period. 4,12,61,63 Although the number of studies involving unilateral ablation (n=4) was smaller than the number involving bilateral ablation (n=14), the similar increase in muscle mass demonstrates the benefits of unilateral surgery, which reduces the number of animals used in experiments and is in line with the goals of the International Council for Laboratory Animal Sciences.…”

“…1,[7][8][9]61 The mean increase in cross-sectional area in comparison to the control was 18.66% in 14 days, demonstrating that compensatory hypertrophy is an effective model for increasing muscle mass. The trend line in Figure 2 shows the percentage increase in muscle mass according to days following surgery: approximately 10% one day after ablation, 38% seven days after ablation and 68% 14 days after ablation.…”

“…At 3 to 5 days, the edema is reduced, followed by an increase in the cross-sectional area of the muscle fibers as well as enzyme activity and protein synthesis, which constitute hypertrophy as an adaptation to the new condition of chronic overload. 1,6,18,61,63 The period of 12 to 15 days was identified as that with the greatest percentage increase in muscle mass in comparison to the control (Figure 3), demonstrating a linear progression (i.e., a progressive gain in muscle mass over the first 15 days after ablation). At 28 days, the authors found no further increase in gene expression related to increased muscle mass, 9,64,65 as demonstrated by the cessation of linear progression and stabilization of the data (Figure 2).…”

“…The muscle adaptation process can be induced by stretching/ immobilization, 44,46 compensatory mechanisms (chronic). 1,[2][3][4][5][6]8,9,12,14,[18][19][20][61][62][63][64][65] and exercise/training. 33,46 Evidence of this is derived from a large number of studies demonstrating that overload leads to an increase in muscle mass and cross-sectional area of the muscle fibers and induces chronic changes in the balance between the synthesis and degradation of proteins.…”

The transcriptional coactivator PGC-1α is dispensable for chronic overload-induced skeletal muscle hypertrophy and metabolic remodeling

“…In fact, inhibition of mTORC1 drastically abrogates plantaris hypertrophy via chronic overload (5), even though muscle size is not affected uniformly by muscle knockout of the mTORC1 inhibitor tuberous sclerosis complex 1 (6). Interestingly, the activity of the mTORC1 protein kinase complex positively correlates with oxidative capacity (7,8).…”