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

Acta neuropathologica, 2016-07, Vol.132 (1), p.127-144 [Peer Reviewed Journal]

The Author(s) 2016 ;COPYRIGHT 2016 Springer ;Springer-Verlag Berlin Heidelberg 2016 ;ISSN: 0001-6322 ;EISSN: 1432-0533 ;DOI: 10.1007/s00401-016-1550-4 ;PMID: 26971100

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Title:
Glycolytic-to-oxidative fiber-type switch and mTOR signaling activation are early-onset features of SBMA muscle modified by high-fat diet
Author: Rocchi, Anna ; Milioto, Carmelo ; Parodi, Sara ; Armirotti, Andrea ; Borgia, Doriana ; Pellegrini, Matteo ; Urciuolo, Anna ; Molon, Sibilla ; Morbidoni, Valeria ; Marabita, Manuela ; Romanello, Vanina ; Gatto, Pamela ; Blaauw, Bert ; Bonaldo, Paolo ; Sambataro, Fabio ; Robins, Diane M. ; Lieberman, Andrew P. ; Sorarù, Gianni ; Vergani, Lodovica ; Sandri, Marco ; Pennuto, Maria
Subjects: Analysis ; Animals ; Atrophy - metabolism ; Atrophy - pathology ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism ; Diet, High-Fat - adverse effects ; Disease Models, Animal ; Disease Progression ; Female ; Genomes ; Glycolysis - physiology ; Humans ; Lipid Metabolism - physiology ; Male ; Medical research ; Medicine ; Medicine & Public Health ; Membrane Potential, Mitochondrial - physiology ; Mice, Transgenic ; Muscle, Skeletal - metabolism ; Muscle, Skeletal - pathology ; Muscular Disorders, Atrophic - metabolism ; Muscular Disorders, Atrophic - pathology ; Neurosciences ; Original Paper ; Oxidation-Reduction ; Pathology ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism ; Protein synthesis ; Random Allocation ; Receptors, Androgen - genetics ; Receptors, Androgen - metabolism ; Signal Transduction ; TOR Serine-Threonine Kinases - metabolism
Is Part Of: Acta neuropathologica, 2016-07, Vol.132 (1), p.127-144
Description: 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.
Publisher: Berlin/Heidelberg: Springer Berlin Heidelberg
Language: English
Identifier: ISSN: 0001-6322
EISSN: 1432-0533
DOI: 10.1007/s00401-016-1550-4
PMID: 26971100
Source: ProQuest One Psychology
MEDLINE
Springer Nature OA/Free Journals
ProQuest Central

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

The Author(s) 2016 ;COPYRIGHT 2016 Springer ;Springer-Verlag Berlin Heidelberg 2016 ;ISSN: 0001-6322 ;EISSN: 1432-0533 ;DOI: 10.1007/s00401-016-1550-4 ;PMID: 26971100

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