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      MEF2 impairment underlies skeletal muscle atrophy in polyglutamine disease

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          Abstract

          Polyglutamine (polyQ) tract expansion leads to proteotoxic misfolding and drives a family of nine diseases. We study spinal and bulbar muscular atrophy (SBMA), a progressive degenerative disorder of the neuromuscular system caused by the polyQ androgen receptor (AR). Using a knock-in mouse model of SBMA, AR113Q mice, we show that E3 ubiquitin ligases which are a hallmark of the canonical muscle atrophy machinery are not induced in AR113Q muscle. Similarly, we find no evidence to suggest dysfunction of signaling pathways that trigger muscle hypertrophy or impairment of the muscle stem cell niche. Instead, we find that skeletal muscle atrophy is characterized by diminished function of the transcriptional regulator Myocyte Enhancer Factor 2 (MEF2), a regulator of myofiber homeostasis. Decreased expression of MEF2 target genes is age- and glutamine tract length-dependent, occurs due to polyQ AR proteotoxicity, and is associated with sequestration of MEF2 into intranuclear inclusions in muscle. Skeletal muscle from R6/2 mice, a model of Huntington disease which develops progressive atrophy, also sequesters MEF2 into inclusions and displays age-dependent loss of MEF2 target genes. Similarly, SBMA patient muscle shows loss of MEF2 target gene expression, and restoring MEF2 activity in AR113Q muscle rescues fiber size and MEF2-regulated gene expression. This work establishes MEF2 impairment as a novel mechanism of skeletal muscle atrophy downstream of toxic polyglutamine proteins and as a therapeutic target for muscle atrophy in these disorders.

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          The online version of this article (10.1007/s00401-020-02156-4) contains supplementary material, which is available to authorized users.

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          Most cited references68

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          DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival.

          The mTORC1 and mTORC2 pathways regulate cell growth, proliferation, and survival. We identify DEPTOR as an mTOR-interacting protein whose expression is negatively regulated by mTORC1 and mTORC2. Loss of DEPTOR activates S6K1, Akt, and SGK1, promotes cell growth and survival, and activates mTORC1 and mTORC2 kinase activities. DEPTOR overexpression suppresses S6K1 but, by relieving feedback inhibition from mTORC1 to PI3K signaling, activates Akt. Consistent with many human cancers having activated mTORC1 and mTORC2 pathways, DEPTOR expression is low in most cancers. Surprisingly, DEPTOR is highly overexpressed in a subset of multiple myelomas harboring cyclin D1/D3 or c-MAF/MAFB translocations. In these cells, high DEPTOR expression is necessary to maintain PI3K and Akt activation and a reduction in DEPTOR levels leads to apoptosis. Thus, we identify a novel mTOR-interacting protein whose deregulated overexpression in multiple myeloma cells represents a mechanism for activating PI3K/Akt signaling and promoting cell survival.
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            Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex.

            Mammalian target of rapamycin (mTOR) is a central regulator of protein synthesis whose activity is modulated by a variety of signals. Energy depletion and hypoxia result in mTOR inhibition. While energy depletion inhibits mTOR through a process involving the activation of AMP-activated protein kinase (AMPK) by LKB1 and subsequent phosphorylation of TSC2, the mechanism of mTOR inhibition by hypoxia is not known. Here we show that mTOR inhibition by hypoxia requires the TSC1/TSC2 tumor suppressor complex and the hypoxia-inducible gene REDD1/RTP801. Disruption of the TSC1/TSC2 complex through loss of TSC1 or TSC2 blocks the effects of hypoxia on mTOR, as measured by changes in the mTOR targets S6K and 4E-BP1, and results in abnormal accumulation of Hypoxia-inducible factor (HIF). In contrast to energy depletion, mTOR inhibition by hypoxia does not require AMPK or LKB1. Down-regulation of mTOR activity by hypoxia requires de novo mRNA synthesis and correlates with increased expression of the hypoxia-inducible REDD1 gene. Disruption of REDD1 abrogates the hypoxia-induced inhibition of mTOR, and REDD1 overexpression is sufficient to down-regulate S6K phosphorylation in a TSC1/TSC2-dependent manner. Inhibition of mTOR function by hypoxia is likely to be important for tumor suppression as TSC2-deficient cells maintain abnormally high levels of cell proliferation under hypoxia.
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              The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription.

              Huntington's Disease (HD) is caused by an expansion of a polyglutamine tract within the huntingtin (htt) protein. Pathogenesis in HD appears to include the cytoplasmic cleavage of htt and release of an amino-terminal fragment capable of nuclear localization. We have investigated potential consequences to nuclear function of a pathogenic amino-terminal region of htt (httex1p) including aggregation, protein-protein interactions, and transcription. httex1p was found to coaggregate with p53 in inclusions generated in cell culture and to interact with p53 in vitro and in cell culture. Expanded httex1p represses transcription of the p53-regulated promoters, p21(WAF1/CIP1) and MDR-1. httex1p was also found to interact in vitro with CREB-binding protein (CBP) and mSin3a, and CBP to localize to neuronal intranuclear inclusions in a transgenic mouse model of HD. These results raise the possibility that expanded repeat htt causes aberrant transcriptional regulation through its interaction with cellular transcription factors which may result in neuronal dysfunction and cell death in HD.
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                Author and article information

                Contributors
                liebermn@umich.edu
                Journal
                Acta Neuropathol
                Acta Neuropathol
                Acta Neuropathologica
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0001-6322
                1432-0533
                18 April 2020
                : 1-18
                Affiliations
                [1 ]GRID grid.214458.e, ISNI 0000000086837370, Department of Pathology, , University of Michigan Medical School, ; Ann Arbor, MI 48109 USA
                [2 ]GRID grid.214458.e, ISNI 0000000086837370, Medical Scientist Training Program, , University of Michigan Medical School, ; Ann Arbor, MI 48109 USA
                [3 ]GRID grid.214458.e, ISNI 0000000086837370, Cellular and Molecular Biology Graduate Program, , University of Michigan Medical School, ; 3510 MSRB1, 1150 W. Medical Center Dr., Ann Arbor, MI 48109 USA
                [4 ]GRID grid.5608.b, ISNI 0000 0004 1757 3470, Department of Biomedical Sciences (DBS), , University of Padova, ; 35131 Padua, Italy
                [5 ]GRID grid.428736.c, Veneto Institute of Molecular Medicine (VIMM), ; 35129 Padua, Italy
                [6 ]GRID grid.5608.b, ISNI 0000 0004 1757 3470, Myology Center (Cir-Myo), , University of Padova, ; 35129 Paduva, Italy
                [7 ]Padova Neuroscience Center (PNC), 35100 Padua, Italy
                [8 ]GRID grid.83440.3b, ISNI 0000000121901201, Huntington’s Disease Centre, Department of Neurodegenerative Disease and UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, , University College London, ; London, WC1N 3BG UK
                [9 ]GRID grid.214458.e, ISNI 0000000086837370, Department of Human Genetics, , University of Michigan Medical School, ; Ann Arbor, MI 48109 USA
                Author information
                http://orcid.org/0000-0001-6336-7991
                Article
                2156
                10.1007/s00401-020-02156-4
                7166004
                31832772
                9bcbef98-2d5b-43c2-b453-5d471c3e7ec2
                © Springer-Verlag GmbH Germany, part of Springer Nature 2020

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 8 January 2020
                : 6 April 2020
                : 7 April 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000065, National Institute of Neurological Disorders and Stroke;
                Award ID: NS055746
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: GM007863
                Award ID: GM007315
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100006801, Horace H. Rackham School of Graduate Studies, University of Michigan;
                Award ID: Rackham Predoctoral Fellowship
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100005725, CHDI Foundation;
                Award ID: CHDI Funding
                Award Recipient :
                Categories
                Original Paper

                Neurology
                Neurology

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