title: Glycolytic-to-oxidative fiber-type switch and mTOR signaling activation are early-onset features of SBMA muscle modified by high-fat diet.
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.
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163, Genoa, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Rocchi
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163, Genoa, Italy.|Dulbecco Telethon Institute, Centre for Integrative Biology, University of Trento, 38123, Trento, Italy.|Dipartimento di Medicina Sperimentale, University of Genova, 16100, Genoa, Italy.
authors.forename: Carmelo
authors.initials: C
authors.lastname: Milioto
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163, Genoa, Italy.|Neurogenetics Branch, NINDS, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Parodi
authors.affiliation: Drug Discovery and Development Department, Istituto Italiano di Tecnologia, 16100, Genoa, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Armirotti
authors.affiliation: Department of Neurosciences, University of Padova, 35100, Padua, Italy.
authors.forename: Doriana
authors.initials: D
authors.lastname: Borgia
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163, Genoa, Italy.|Department of Experimental Medicine (DIMES)-Biochemistry Section, University of Genova, Viale Benedetto XV, 1, 16132, Genoa, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Pellegrini
authors.affiliation: Department of Molecular Medicine, University of Padova, 35131, Padua, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Urciuolo
authors.affiliation: Department of Molecular Medicine, University of Padova, 35131, Padua, Italy.
authors.forename: Sibilla
authors.initials: S
authors.lastname: Molon
authors.affiliation: Department of Molecular Medicine, University of Padova, 35131, Padua, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Morbidoni
authors.affiliation: Venetian Institute of Molecular Medicine, Department of Biomedical Science, University of Padova, 35100, Padua, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Marabita
authors.affiliation: Venetian Institute of Molecular Medicine, Department of Biomedical Science, University of Padova, 35100, Padua, Italy.
authors.forename: Vanina
authors.initials: V
authors.lastname: Romanello
authors.affiliation: High-Throughput Screening Core Facility, Centre for Integrative Biology, University of Trento, 38123, Trento, Italy.
authors.forename: Pamela
authors.initials: P
authors.lastname: Gatto
authors.affiliation: Venetian Institute of Molecular Medicine, Department of Biomedical Science, University of Padova, 35100, Padua, Italy.
authors.forename: Bert
authors.initials: B
authors.lastname: Blaauw
authors.affiliation: Department of Molecular Medicine, University of Padova, 35131, Padua, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bonaldo
authors.affiliation: Department of Experimental and Clinical Medical Sciences (DISM), University of Udine, 33100, Udine, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Sambataro
authors.affiliation: Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
authors.forename: Diane M
authors.initials: DM
authors.lastname: Robins
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Lieberman
authors.affiliation: Department of Neurosciences, University of Padova, 35100, Padua, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Sorarù
authors.affiliation: Department of Neurosciences, University of Padova, 35100, Padua, Italy.
authors.forename: Lodovica
authors.initials: L
authors.lastname: Vergani
authors.affiliation: Venetian Institute of Molecular Medicine, Department of Biomedical Science, University of Padova, 35100, Padua, Italy.|Telethon Institute of Genetic and Medicine, Pozzuoli, 80100, Naples, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Sandri
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163, Genoa, Italy. MPennuto@Dti.Telethon.it.|Dulbecco Telethon Institute, Centre for Integrative Biology, University of Trento, 38123, Trento, Italy. MPennuto@Dti.Telethon.it.
authors.forename: Maria
authors.identifier: 0000-0001-8634-0767
authors.initials: M
authors.lastname: Pennuto
mesh_terms: D000818:Animals; D001284:Atrophy / Q000378:metabolism / Q000473:pathology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006019:Glycolysis / Q000502:physiology; D006801:Humans; D050356:Lipid Metabolism / Q000502:physiology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D020966:Muscular Disorders, Atrophic / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism; D011897:Random Allocation; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D011944:Receptors, Androgen; C484068:Tcfeb protein, mouse; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases
keywords: Androgen receptor; High-fat diet; PGC1α; Rapamycin; Skeletal muscle; Spinal and bulbar muscular atrophy; mTOR