Activation of eIF4E‐binding‐protein‐1 rescues mTORC1‐induced sarcopenia by expanding lysosomal degradation capacity

Abstract

Background Chronic mTORC1 activation in skeletal muscle is linked with age‐associated loss of muscle mass and strength, known as sarcopenia. Genetic activation of mTORC1 by conditionally ablating mTORC1 upstream inhibitor TSC1 in skeletal muscle accelerates sarcopenia development in adult mice. Conversely, genetic suppression of mTORC1 downstream effectors of protein synthesis delays sarcopenia in natural aging mice. mTORC1 promotes protein synthesis by activating ribosomal protein S6 kinases (S6Ks) and inhibiting eIF4E‐binding proteins (4EBPs). Whole‐body knockout of S6K1 or muscle‐specific over‐expression of a 4EBP1 mutant transgene (4EBP1mt), which is resistant to mTORC1‐mediated inhibition, ameliorates muscle loss with age and preserves muscle function by enhancing mitochondria activities, despite both transgenic mice showing retarded muscle growth at a young age. Why repression of mTORC1‐mediated protein synthesis can mitigate progressive muscle atrophy and dysfunction with age remains unclear. Methods Mice with myofiber‐specific knockout of TSC1 (TSC1mKO), in which mTORC1 is hyperactivated in fully differentiated myofibers, were used as a mouse model of sarcopenia. To elucidate the role of mTORC1‐mediated protein synthesis in regulating muscle mass and physiology, we bred the 4EBP1mt transgene or S6k1 floxed mice into the TSC1mKO mouse background to generate 4EBP1mt‐TSC1mKO or S6K1‐TSC1mKO mice, respectively. Functional and molecular analyses were performed to assess their role in sarcopenia development. Results Here, we show that 4EBP1mt‐TSC1mKO, but not S6K1‐TSC1mKO, preserved muscle mass (36.7% increase compared with TSC1mKO, P < 0.001) and strength (36.8% increase compared with TSC1mKO, P < 0.01) at the level of control mice. Mechanistically, 4EBP1 activation suppressed aberrant protein synthesis (two‐fold reduction compared with TSC1mKO, P < 0.05) and restored autophagy flux without relieving mTORC1‐mediated inhibition of ULK1, an upstream activator of autophagosome initiation. We discovered a previously unidentified phenotype of lysosomal failure in TSC1mKO mouse muscle, in which the lysosomal defect was also conserved in the naturally aged mouse muscle, whereas 4EBP1 activation enhanced lysosomal protease activities to compensate for impaired autophagy induced by mTORC1 hyperactivity. Consequently, 4EBP1 activation relieved oxidative stress to prevent toxic aggregate accumulation (0.5‐fold reduction compared with TSC1mKO, P < 0.05) in muscle and restored mitochondrial homeostasis and function. Conclusions We identify 4EBP1 as a communication hub coordinating protein synthesis and degradation to protect proteostasis, revealing therapeutic potential for activating lysosomal degradation to mitigate sarcopenia.

Targeting phosphatase DUSP22 ameliorates skeletal muscle wasting via Akt independent JNK-FOXO3a repression

“…This may be advantageous for developing therapeutic approaches that target FOXO3a independently of the IGF-1-PI3K-Akt pathway due to potential side effects associated with PI3k-Akt activation [46, 47]. In addition, over-activation of protein synthesis, which is a downstream target of IGF-1-PI3K-Akt, has recently been observed in aging-related skeletal muscle wasting [48, 49]. Strategies to further increase protein synthesis in geriatric muscle may worsen proteostatic stress [48].…”

Structural and Dynamical Analyses of Apo and Cap-binding eIF4E: Anin silicoStudy

“…1 Therefore, abundance of eIF4E is essential for translation of mRNAs coding for proteins that play critical roles in regulating cellular functions such as proliferation, malignant transformation, 2–7 mitochondrial dynamics, 8,9 learning and memory, 10–14 and aging. 15,16 Consistently, studies that increased or reduced eIF4E expression and/or its cellular inhibitors and activators demonstrated that non-physiologic activation of eIF4E significantly contributes to pathophysiology of many human disorders including cancer, 17,18 diabetes, 19,20 autism related learning deficits, 21–23 Parkinson’s, 24 Huntington’s 25 and Alzheimer’s diseases 26 and play a causative role in fragile-X mental retardation syndrome. 27,28 These studies indicate that reducing eIF4E expression/activity may be beneficial for the management of an array of human disorders.…”

Modulation of protease expression by the transcription factor Ptx1/PITX regulates protein quality control during aging

“…Skeletal muscle is one of the tissues with the highest challenges to protein quality control due to contraction-associated mechanical protein unfolding and oxidative damage. 19 - 23 In both Drosophila and mammals, 24 skeletal muscle aging is characterized by a prominent loss of protein quality control, 20 , 21 , 25 - 28 as indicated by the progressive accumulation of poly-ubiquitinated protein aggregates with aging and by the age-related increase in ubiquitinated proteins detected in detergent-insoluble fractions ( Figure 1A ). Although dysfunction of the autophagy-lysosome and ubiquitin-proteasome systems has been shown to contribute to loss of proteostasis in muscle with aging, 20 , 29 - 31 it is largely unknown whether other proteolytic systems contribute to the derangement of muscle proteostasis.…”