Proteasome-dependent Activation of Mammalian Target of Rapamycin Complex 1 (mTORC1) Is Essential for Autophagy Suppression and Muscle Remodeling Following Denervation

Quy, Pham Nguyen; Kuma, Akiko; Pierre, Philippe; Mizushima, Noboru

doi:10.1074/jbc.m112.399949

Cited by 96 publications

(71 citation statements)

References 44 publications

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“…Surprisingly, mTORC1 was activated 3 days after denervation in CTRL mice. These results are in agreement with those obtained in other studies,45, 48 indicating that mTORC1 activation could be an adaptive or compensatory mechanism following denervation. However, in those studies, the inactivation of mTORC1 by rapamycin did not rescue the atrophy phenotype, suggesting that the activation of mTORC1 is essential to maintain the activity of protein synthesis in serious situations of denervation.…”

Section: Discussionsupporting

confidence: 93%

“…As expected from previous studies,23, 44, 45, 46 the ubiquitin–proteasome and the lysosomal–autophagy pathways were activated in TIB muscle 3 days after denervation. Our results are in agreement with previous findings showing that an inhibition of the ubiquitin–proteasome system reduces muscle atrophy in a model of denervation in rats 47.…”

Section: Discussionsupporting

confidence: 88%

“…However, in those studies, the inactivation of mTORC1 by rapamycin did not rescue the atrophy phenotype, suggesting that the activation of mTORC1 is essential to maintain the activity of protein synthesis in serious situations of denervation. This activation is possibly the consequence of a high ubiquitin–proteasome activity associated with the release of a large amount of amino acids 45. In our context, this activation of mTORC1 was not found in mice treated with urolithin B.…”

Section: Discussionmentioning

confidence: 49%

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Urolithin B, a newly identified regulator of skeletal muscle mass

Rodriguez

Pierre

Naslain

et al. 2017

J cachexia sarcopenia muscle

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BackgroundThe control of muscle size is an essential feature of health. Indeed, skeletal muscle atrophy leads to reduced strength, poor quality of life, and metabolic disturbances. Consequently, strategies aiming to attenuate muscle wasting and to promote muscle growth during various (pathological) physiological states like sarcopenia, immobilization, malnutrition, or cachexia are needed to address this extensive health issue. In this study, we tested the effects of urolithin B, an ellagitannin‐derived metabolite, on skeletal muscle growth.MethodsC2C12 myotubes were treated with 15 μM of urolithin B for 24 h. For in vivo experiments, mice were implanted with mini‐osmotic pumps delivering continuously 10 μg/day of urolithin B during 28 days. Muscle atrophy was studied in mice with a sciatic nerve denervation receiving urolithin B by the same way.ResultsOur experiments reveal that urolithin B enhances the growth and differentiation of C2C12 myotubes by increasing protein synthesis and repressing the ubiquitin–proteasome pathway. Genetic and pharmacological arguments support an implication of the androgen receptor. Signalling analyses suggest a crosstalk between the androgen receptor and the mTORC1 pathway, possibly via AMPK. In vivo experiments confirm that urolithin B induces muscle hypertrophy in mice and reduces muscle atrophy after the sciatic nerve section.ConclusionsThis study highlights the potential usefulness of urolithin B for the treatment of muscle mass loss associated with various (pathological) physiological states.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 49%

See 1 more Smart Citation

Urolithin B, a newly identified regulator of skeletal muscle mass

Rodriguez

Pierre

Naslain

et al. 2017

J cachexia sarcopenia muscle

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“…The primary target of rapamycin is mTORC1, which has been shown to play an important role in muscle protein synthesis and remodeling following acute, injury-induced denervation (Bentzinger et al, 2013, Quy et al, 2013). While muscle denervation is not a prominent pathology in young neuropathic mice (Nicks et al, 2013), it has been suggested that muscle innervation might not develop normally in some neuropathic animals (Meekins et al, 2004).…”

Section: Resultsmentioning

confidence: 99%

Rapamycin improves peripheral nerve myelination while it fails to benefit neuromuscular performance in neuropathic mice

Nicks

Lee

Harris

et al. 2014

Neurobiology of Disease

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Charcot-Marie-Tooth disease type 1A (CMT1A) is a hereditary peripheral neuropathy characterized by progressive demyelination and distal muscle weakness. Abnormal expression of peripheral myelin protein 22 (PMP22) has been linked to CMT1A and is modeled by Trembler J (TrJ) mice, which carry the same leucine to proline substitution in PMP22 as affected pedigrees. Pharmacologic modulation of autophagy by rapamycin in neuron-Schwann cell explant cultures from neuropathic mice reduced PMP22 aggregate formation and improved myelination. Here we asked whether rapamycin administration by food supplementation, or intraperitoneal injection, could alleviate the neuropathic phenotype of affected mice and improve neuromuscular performance. Cohorts of male and female wild type (Wt) and TrJ mice were assigned to placebo or rapamycin treatment starting at 2 or 4 months of age and tested monthly on the rotarod. While neither long-term feeding (8 or 10 months) on rapamycin-enriched diet, or short term injection (2 months) of rapamycin improved locomotor performance of the neuropathic mice, both regimen benefited peripheral nerve myelination. Together, these results indicate that while treatment with rapamycin benefits the myelination capacity of neuropathic Schwann cells, this intervention does not improve neuromuscular function. The observed outcome might be the result of the differential response of nerve and skeletal muscle tissue to rapamycin.

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“…Mouse embryonic fibroblasts (MEFs). Rabbit polyclonal antibody against LC3 (NM1) was described previously [27]. Other LC3 antibodies (e.g., anti-LC3 pAb, MBL, cat.…”

Section: Cell Linesmentioning

confidence: 99%