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Acta Neuropathol. 2016 Jul;132(1):127-44. doi: 10.1007/s00401-016-1550-4. Epub 2016 Mar 12.

Glycolytic-to-oxidative fiber-type switch and mTOR signaling activation are early-onset features of SBMA muscle modified by high-fat diet.

Author information

1
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163, Genoa, Italy.
2
Dulbecco Telethon Institute, Centre for Integrative Biology, University of Trento, 38123, Trento, Italy.
3
Dipartimento di Medicina Sperimentale, University of Genova, 16100, Genoa, Italy.
4
Neurogenetics Branch, NINDS, National Institutes of Health, Bethesda, MD, 20892, USA.
5
Drug Discovery and Development Department, Istituto Italiano di Tecnologia, 16100, Genoa, Italy.
6
Department of Neurosciences, University of Padova, 35100, Padua, Italy.
7
Department of Experimental Medicine (DIMES)-Biochemistry Section, University of Genova, Viale Benedetto XV, 1, 16132, Genoa, Italy.
8
Department of Molecular Medicine, University of Padova, 35131, Padua, Italy.
9
Venetian Institute of Molecular Medicine, Department of Biomedical Science, University of Padova, 35100, Padua, Italy.
10
High-Throughput Screening Core Facility, Centre for Integrative Biology, University of Trento, 38123, Trento, Italy.
11
Department of Experimental and Clinical Medical Sciences (DISM), University of Udine, 33100, Udine, Italy.
12
Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
13
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
14
Telethon Institute of Genetic and Medicine, Pozzuoli, 80100, Naples, Italy.
15
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163, Genoa, Italy. MPennuto@Dti.Telethon.it.
16
Dulbecco Telethon Institute, Centre for Integrative Biology, University of Trento, 38123, Trento, Italy. MPennuto@Dti.Telethon.it.

Abstract

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by the expansion of a polyglutamine tract in the androgen receptor (AR). The mechanism by which expansion of polyglutamine in AR causes muscle atrophy is unknown. Here, we investigated pathological pathways underlying muscle atrophy in SBMA knock-in mice and patients. We show that glycolytic muscles were more severely affected than oxidative muscles in SBMA knock-in mice. Muscle atrophy was associated with early-onset, progressive glycolytic-to-oxidative fiber-type switch. Whole genome microarray and untargeted lipidomic analyses revealed enhanced lipid metabolism and impaired glycolysis selectively in muscle. These metabolic changes occurred before denervation and were associated with a concurrent enhancement of mechanistic target of rapamycin (mTOR) signaling, which induced peroxisome proliferator-activated receptor γ coactivator 1 alpha (PGC1α) expression. At later stages of disease, we detected mitochondrial membrane depolarization, enhanced transcription factor EB (TFEB) expression and autophagy, and mTOR-induced protein synthesis. Several of these abnormalities were detected in the muscle of SBMA patients. Feeding knock-in mice a high-fat diet (HFD) restored mTOR activation, decreased the expression of PGC1α, TFEB, and genes involved in oxidative metabolism, reduced mitochondrial abnormalities, ameliorated muscle pathology, and extended survival. These findings show early-onset and intrinsic metabolic alterations in SBMA muscle and link lipid/glucose metabolism to pathogenesis. Moreover, our results highlight an HFD regime as a promising approach to support SBMA patients.

KEYWORDS:

Androgen receptor; High-fat diet; PGC1α; Rapamycin; Skeletal muscle; Spinal and bulbar muscular atrophy; mTOR

PMID:
26971100
PMCID:
PMC4911374
DOI:
10.1007/s00401-016-1550-4
[Indexed for MEDLINE]
Free PMC Article

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