PMID- 26971100
OWN - NLM
STAT- MEDLINE
DCOM- 20171204
LR  - 20220129
IS  - 1432-0533 (Electronic)
IS  - 0001-6322 (Print)
IS  - 0001-6322 (Linking)
VI  - 132
IP  - 1
DP  - 2016 Jul
TI  - Glycolytic-to-oxidative fiber-type switch and mTOR signaling activation are 
      early-onset features of SBMA muscle modified by high-fat diet.
PG  - 127-44
LID - 10.1007/s00401-016-1550-4 [doi]
AB  - 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 gamma coactivator 1 alpha (PGC1alpha) 
      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 PGC1alpha, 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.
FAU - Rocchi, Anna
AU  - Rocchi A
AD  - Department of Neuroscience and Brain Technologies, Istituto Italiano di 
      Tecnologia, 16163, Genoa, Italy.
FAU - Milioto, Carmelo
AU  - Milioto C
AD  - Department of Neuroscience and Brain Technologies, Istituto Italiano di 
      Tecnologia, 16163, Genoa, Italy.
AD  - Dulbecco Telethon Institute, Centre for Integrative Biology, University of 
      Trento, 38123, Trento, Italy.
AD  - Dipartimento di Medicina Sperimentale, University of Genova, 16100, Genoa, Italy.
FAU - Parodi, Sara
AU  - Parodi S
AD  - Department of Neuroscience and Brain Technologies, Istituto Italiano di 
      Tecnologia, 16163, Genoa, Italy.
AD  - Neurogenetics Branch, NINDS, National Institutes of Health, Bethesda, MD, 20892, 
      USA.
FAU - Armirotti, Andrea
AU  - Armirotti A
AD  - Drug Discovery and Development Department, Istituto Italiano di Tecnologia, 
      16100, Genoa, Italy.
FAU - Borgia, Doriana
AU  - Borgia D
AD  - Department of Neurosciences, University of Padova, 35100, Padua, Italy.
FAU - Pellegrini, Matteo
AU  - Pellegrini M
AD  - Department of Neuroscience and Brain Technologies, Istituto Italiano di 
      Tecnologia, 16163, Genoa, Italy.
AD  - Department of Experimental Medicine (DIMES)-Biochemistry Section, University of 
      Genova, Viale Benedetto XV, 1, 16132, Genoa, Italy.
FAU - Urciuolo, Anna
AU  - Urciuolo A
AD  - Department of Molecular Medicine, University of Padova, 35131, Padua, Italy.
FAU - Molon, Sibilla
AU  - Molon S
AD  - Department of Molecular Medicine, University of Padova, 35131, Padua, Italy.
FAU - Morbidoni, Valeria
AU  - Morbidoni V
AD  - Department of Molecular Medicine, University of Padova, 35131, Padua, Italy.
FAU - Marabita, Manuela
AU  - Marabita M
AD  - Venetian Institute of Molecular Medicine, Department of Biomedical Science, 
      University of Padova, 35100, Padua, Italy.
FAU - Romanello, Vanina
AU  - Romanello V
AD  - Venetian Institute of Molecular Medicine, Department of Biomedical Science, 
      University of Padova, 35100, Padua, Italy.
FAU - Gatto, Pamela
AU  - Gatto P
AD  - High-Throughput Screening Core Facility, Centre for Integrative Biology, 
      University of Trento, 38123, Trento, Italy.
FAU - Blaauw, Bert
AU  - Blaauw B
AD  - Venetian Institute of Molecular Medicine, Department of Biomedical Science, 
      University of Padova, 35100, Padua, Italy.
FAU - Bonaldo, Paolo
AU  - Bonaldo P
AD  - Department of Molecular Medicine, University of Padova, 35131, Padua, Italy.
FAU - Sambataro, Fabio
AU  - Sambataro F
AD  - Department of Experimental and Clinical Medical Sciences (DISM), University of 
      Udine, 33100, Udine, Italy.
FAU - Robins, Diane M
AU  - Robins DM
AD  - Department of Human Genetics, University of Michigan Medical School, Ann Arbor, 
      MI, 48109, USA.
FAU - Lieberman, Andrew P
AU  - Lieberman AP
AD  - Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, 
      48109, USA.
FAU - Soraru, Gianni
AU  - Soraru G
AD  - Department of Neurosciences, University of Padova, 35100, Padua, Italy.
FAU - Vergani, Lodovica
AU  - Vergani L
AD  - Department of Neurosciences, University of Padova, 35100, Padua, Italy.
FAU - Sandri, Marco
AU  - Sandri M
AD  - Venetian Institute of Molecular Medicine, Department of Biomedical Science, 
      University of Padova, 35100, Padua, Italy.
AD  - Telethon Institute of Genetic and Medicine, Pozzuoli, 80100, Naples, Italy.
FAU - Pennuto, Maria
AU  - Pennuto M
AUID- ORCID: 0000-0001-8634-0767
AD  - Department of Neuroscience and Brain Technologies, Istituto Italiano di 
      Tecnologia, 16163, Genoa, Italy. MPennuto@Dti.Telethon.it.
AD  - Dulbecco Telethon Institute, Centre for Integrative Biology, University of 
      Trento, 38123, Trento, Italy. MPennuto@Dti.Telethon.it.
LA  - eng
GR  - 282310/ERC_/European Research Council/International
GR  - P30 DK020572/DK/NIDDK NIH HHS/United States
GR  - R01 NS055746/NS/NINDS NIH HHS/United States
GR  - TCP12013/TI_/Telethon/Italy
PT  - Journal Article
DEP - 20160312
PL  - Germany
TA  - Acta Neuropathol
JT  - Acta neuropathologica
JID - 0412041
RN  - 0 (Basic Helix-Loop-Helix Leucine Zipper Transcription Factors)
RN  - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha)
RN  - 0 (Ppargc1a protein, mouse)
RN  - 0 (Receptors, Androgen)
RN  - 0 (Tcfeb protein, mouse)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Atrophy/metabolism/pathology
MH  - Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism
MH  - Diet, High-Fat/*adverse effects
MH  - Disease Models, Animal
MH  - Disease Progression
MH  - Female
MH  - *Glycolysis/physiology
MH  - Humans
MH  - Lipid Metabolism/physiology
MH  - Male
MH  - Membrane Potential, Mitochondrial/physiology
MH  - Mice, Transgenic
MH  - Muscle, Skeletal/*metabolism/pathology
MH  - Muscular Disorders, Atrophic/*metabolism/pathology
MH  - Oxidation-Reduction
MH  - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism
MH  - Random Allocation
MH  - Receptors, Androgen/genetics/metabolism
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases/*metabolism
PMC - PMC4911374
OTO - NOTNLM
OT  - Androgen receptor
OT  - High-fat diet
OT  - PGC1alpha
OT  - Rapamycin
OT  - Skeletal muscle
OT  - Spinal and bulbar muscular atrophy
OT  - mTOR
EDAT- 2016/03/14 06:00
MHDA- 2017/12/05 06:00
PMCR- 2016/03/12
CRDT- 2016/03/14 06:00
PHST- 2015/10/28 00:00 [received]
PHST- 2016/02/19 00:00 [accepted]
PHST- 2016/02/19 00:00 [revised]
PHST- 2016/03/14 06:00 [entrez]
PHST- 2016/03/14 06:00 [pubmed]
PHST- 2017/12/05 06:00 [medline]
PHST- 2016/03/12 00:00 [pmc-release]
AID - 10.1007/s00401-016-1550-4 [pii]
AID - 1550 [pii]
AID - 10.1007/s00401-016-1550-4 [doi]
PST - ppublish
SO  - Acta Neuropathol. 2016 Jul;132(1):127-44. doi: 10.1007/s00401-016-1550-4. Epub 
      2016 Mar 12.