mTORC1 Regulates Mitochondrial Integrated Stress Response and Mitochondrial Myopathy Progression

Khan, Nahid Akhtar; Nikkanen, Joni; Yatsuga, Shuichi; Jackson, Christopher B.; Wang, Liya; Pradhan, Swagat; Kivelä, Riikka; Pessia, Alberto; Velagapudi, Vidya; Suomalainen, Anu

doi:10.1016/j.cmet.2017.07.007

Cited by 322 publications

(404 citation statements)

References 47 publications

(76 reference statements)

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“…We found the full set of ~100 metabolites very informative, and a previous study in mitochondrial myopathy mice supported the biomarker potential of a semiquantitative metabolomic analysis in follow‐up of therapy effect: after treatment with rapamycin, the metabolomes of wild‐type and affected mice shifted from separate clusters to overlap (Khan et al , ). However, we also identified here a minimal set of four individual metabolites that were enough to distinguish MDs from other muscle‐manifesting disorders as a “multi‐biomarker”: cystathionine, sorbitol, myoinositol and alanine.…”

Section: Discussionsupporting

confidence: 77%

“…Our finding of the similarity of blood metabolomes of the primary MDs and IBM suggests that mitochondrial dysfunction drives the metabolic changes in IBM reflected in the blood. These findings propose that intervention strategies of mitochondrial biogenesis, NAD + ‐boosters or rapamycin, suggested to be beneficial for mitochondrial myopathies in mice (Viscomi et al , ; Yatsuga & Suomalainen, ; Cerutti et al , ; Khan et al , , ), should be evaluated also in IBM.…”

Section: Discussionmentioning

confidence: 99%

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Metabolomes of mitochondrial diseases and inclusion body myositis patients: treatment targets and biomarkers

et al. 2018

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Mitochondrial disorders (MDs) are inherited multi‐organ diseases with variable phenotypes. Inclusion body myositis (IBM), a sporadic inflammatory muscle disease, also shows mitochondrial dysfunction. We investigated whether primary and secondary MDs modify metabolism to reveal pathogenic pathways and biomarkers. We investigated metabolomes of 25 mitochondrial myopathy or ataxias patients, 16 unaffected carriers, six IBM and 15 non‐mitochondrial neuromuscular disease (NMD) patients and 30 matched controls. MD and IBM metabolomes clustered separately from controls and NMDs. MDs and IBM showed transsulfuration pathway changes; creatine and niacinamide depletion marked NMDs, IBM and infantile‐onset spinocerebellar ataxia (IOSCA). Low blood and muscle arginine was specific for patients with m.3243A>G mutation. A four‐metabolite blood multi‐biomarker (sorbitol, alanine, myoinositol, cystathionine) distinguished primary MDs from others (76% sensitivity, 95% specificity). Our omics approach identified pathways currently used to treat NMDs and mitochondrial stroke‐like episodes and proposes nicotinamide riboside in MDs and IBM, and creatine in IOSCA and IBM as novel treatment targets. The disease‐specific metabolic fingerprints are valuable “multi‐biomarkers” for diagnosis and promising tools for follow‐up of disease progression and treatment effect.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Metabolomes of mitochondrial diseases and inclusion body myositis patients: treatment targets and biomarkers

et al. 2018

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“…It is tempting to speculate that mTORmKOKI muscles are mechanistically unable to induce FGF21. In support of this notion, FGF21 has been shown to be under mTORC1 control because its transcriptional induction is rapamycin‐sensitive and is directly mediated by transcription factors themselves regulated by mTOR, such as PPARs, ATF4, and ChREBP …”

Section: Discussionmentioning

confidence: 94%

Lack of muscle mTOR kinase activity causes early onset myopathy and compromises whole‐body homeostasis

Zhang

Conjard-Duplany

Moncollin

et al. 2018

J cachexia sarcopenia muscle

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Background The protein kinase mechanistic target of rapamycin (mTOR) controls cellular growth and metabolism. Although balanced mTOR signalling is required for proper muscle homeostasis, partial mTOR inhibition by rapamycin has beneficial effects on various muscle disorders and age‐related pathologies. Besides, more potent mTOR inhibitors targeting mTOR catalytic activity have been developed and are in clinical trials. However, the physiological impact of loss of mTOR catalytic activity in skeletal muscle is currently unknown. Methods We have generated the mTORmKOKI mouse model in which conditional loss of mTOR is concomitant with expression of kinase inactive mTOR in skeletal muscle. We performed a comparative phenotypic and biochemical analysis of mTORmKOKI mutant animals with muscle‐specific mTOR knockout (mTORmKO) littermates. Results In striking contrast with mTORmKO littermates, mTORmKOKI mice developed an early onset rapidly progressive myopathy causing juvenile lethality. More than 50% mTORmKOKI mice died before 8 weeks of age, and none survived more than 12 weeks, while mTORmKO mice died around 7 months of age. The growth rate of mTORmKOKI mice declined beyond 1 week of age, and the animals showed profound alterations in body composition at 4 weeks of age. At this age, their body weight was 64% that of mTORmKO mice ( P < 0.001) due to significant reduction in lean and fat mass. The mass of isolated muscles from mTORmKOKI mice was remarkably decreased by 38–56% ( P < 0.001) as compared with that from mTORmKO mice. Histopathological analysis further revealed exacerbated dystrophic features and metabolic alterations in both slow/oxidative and fast/glycolytic muscles from mTORmKOKI mice. We show that the severity of the mTORmKOKI as compared with the mild mTORmKO phenotype is due to more robust suppression of muscle mTORC1 signalling leading to stronger alterations in protein synthesis, oxidative metabolism, and autophagy. This was accompanied with stronger feedback activation of PKB/Akt and dramatic down‐regulation of glycogen phosphorylase expression (0.16‐fold in tibialis anterior muscle, P < 0.01), thus causing features of glycogen storage disease type V. Conclusions Our study demonstrates a critical role for muscle mTOR catalytic activity in the regulation of whole‐body growth and homeostasis. We suggest that skeletal muscle targeting with mTOR catalytic inhibitors may have detrimental effects. The mTORmKOKI mutant mouse provides an animal model for the pathophysiological understanding of muscle mTOR activity inhibition as well as for mechanistic investigation of the influence of skeletal muscle perturbations on whole‐body homeostasis.

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“…Rapamycin has recently been reported as beneficial in mouse and cellular models of mitochondrial disease (Johnson et al , , ; Zheng et al , ; Felici et al , ; Khan et al , ; Siegmund et al , ). The mechanisms underlying these effects are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

“…The mechanisms underlying these effects are poorly understood. Although activation of autophagy upon rapamycin treatment has been reported in some of these studies (Johnson et al , ; Khan et al , ), others failed to detect it (Felici et al , ; Siegmund et al , ), but all were based on the measurement of autophagy markers at the steady state, whereas autophagic flux was not investigated in detail.…”

Section: Introductionmentioning

confidence: 99%

Rapamycin rescues mitochondrial myopathy via coordinated activation of autophagy and lysosomal biogenesis

et al. 2018

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The mTOR inhibitor rapamycin ameliorates the clinical and biochemical phenotype of mouse, worm, and cellular models of mitochondrial disease, via an unclear mechanism. Here, we show that prolonged rapamycin treatment improved motor endurance, corrected morphological abnormalities of muscle, and increased cytochrome c oxidase (COX) activity of a muscle‐specific Cox15 knockout mouse (Cox15 sm/sm). Rapamycin treatment restored autophagic flux, which was impaired in naïve Cox15 sm/sm muscle, and reduced the number of damaged mitochondria, which accumulated in untreated Cox15 sm/sm mice. Conversely, rilmenidine, an mTORC1‐independent autophagy inducer, was ineffective on the myopathic features of Cox15 sm/sm animals. This stark difference supports the idea that inhibition of mTORC1 by rapamycin has a key role in the improvement of the mitochondrial function in Cox15 sm/sm muscle. In contrast to rilmenidine, rapamycin treatment also activated lysosomal biogenesis in muscle. This effect was associated with increased nuclear localization of TFEB, a master regulator of lysosomal biogenesis, which is inhibited by mTORC1‐dependent phosphorylation. We propose that the coordinated activation of autophagic flux and lysosomal biogenesis contribute to the effective clearance of dysfunctional mitochondria by rapamycin.

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mTORC1 Regulates Mitochondrial Integrated Stress Response and Mitochondrial Myopathy Progression

Cited by 322 publications

References 47 publications

Metabolomes of mitochondrial diseases and inclusion body myositis patients: treatment targets and biomarkers

Metabolomes of mitochondrial diseases and inclusion body myositis patients: treatment targets and biomarkers

Lack of muscle mTOR kinase activity causes early onset myopathy and compromises whole‐body homeostasis

Rapamycin rescues mitochondrial myopathy via coordinated activation of autophagy and lysosomal biogenesis

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