Dual roles of mTORC1-dependent activation of the ubiquitin-proteasome system in muscle proteostasis

Abstract

Muscle size is controlled by the PI3K-PKB/Akt-mTORC1-FoxO pathway, which integrates signals from growth factors, energy and amino acids to activate protein synthesis and inhibit protein breakdown. While mTORC1 activity is necessary for PKB/Akt-induced muscle hypertrophy, its constant activation alone induces muscle atrophy. Here we show that this paradox is based on mTORC1 activity promoting protein breakdown through the ubiquitin-proteasome system (UPS) by simultaneously inducing ubiquitin E3 ligase expression via feedback inhibition of PKB/Akt and proteasome biogenesis via Nuclear Factor Erythroid 2-Like 1 (Nrf1). Muscle growth was restored by reactivation of PKB/Akt, but not by Nrf1 knockdown, implicating ubiquitination as the limiting step. However, both PKB/Akt activation and proteasome depletion by Nrf1 knockdown led to an immediate disruption of proteome integrity with rapid accumulation of damaged material. These data highlight the physiological importance of mTORC1-mediated PKB/Akt inhibition and point to juxtaposed roles of the UPS in atrophy and proteome integrity.

Temporal regulation of the Mediator complex during muscle proliferation, differentiation, regeneration, aging, and disease

“…RNA-seq data were obtained from public repositories. RNA-Seq data from muscle stem cells pre-and post-injury were collected from GSE189073 (Dong et al, 2022) and RNA-Seq reads for mouse muscle aging model were collected from GSE139204 (Ham et al, 2020;Ham et al, 2022;Kaiser et al, 2022). FASTQ files were obtained using the fastq-dump function in the sra-tools package (v3.0.8).…”

“…To determine how Mediator complex subunit expression is altered in aging muscles and could contribute to the muscle aging process we analyzed RNA-seq data from 10-and 30-months-old male mouse muscles. Raw sequencing data were used for this analysis (GSE139204) (Ham et al, 2020;Ham et al, 2022;Kaiser et al, 2022). Surprisingly, the expression of most Mediator complex subunits was unaffected by aging in TA muscles (Figure 6A, Supplementary Table S3) as well as in gastrocnemius muscles (Supplementary Figure S6A, Supplementary Table S4), soleus muscles (Supplementary Figure S6B, Supplementary Table S5), and in triceps muscles (Supplementary Figure S6C, Supplementary Table S6).…”

Ubiquitin Ligases in Longevity and Aging Skeletal Muscle

“…Indeed, sustained mTORC1 hyperactivation is observed to induce the molecular signatures of age-related muscle loss [ 70 , 71 ]. Recent evidence suggests that mTORC1 might also play an important role in the activation of the UPS system and overall muscle proteostasis [ 72 ]. The mTORC1 pathway is an example of the cellular and molecular mechanisms which contribute to the age-related loss of muscle mass but other pathways have been implicated in longevity, which help modulate skeletal muscle maintenance [ 3 ].…”