Rescue of Metabolic Alterations in AR113Q Skeletal Muscle by Peripheral Androgen Receptor Gene Silencing.
Spinal and bulbar muscular atrophy (SBMA), a progressive degenerative disorder, is caused by a CAG/glutamine expansion in the androgen receptor (polyQ AR). Recent studies demonstrate that skeletal muscle is an important site of toxicity that contributes to the SBMA phenotype. Here, we sought to identify critical pathways altered in muscle that underlie disease manifestations in AR113Q mice. This led to the unanticipated identification of gene expression changes affecting regulators of carbohydrate metabolism, similar to those triggered by denervation. AR113Q muscle exhibits diminished glycolysis, altered mitochondria, and an impaired response to exercise. Strikingly, the expression of genes regulating muscle energy metabolism is rescued following peripheral polyQ AR gene silencing by antisense oligonucleotides (ASO), a therapeutic strategy that alleviates disease. Our data establish the occurrence of a metabolic imbalance in SBMA muscle triggered by peripheral expression of the polyQ AR and indicate that alterations in energy utilization contribute to non-neuronal disease manifestations.
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Elisa
E
Giorgetti
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Zhigang
Z
Yu
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Jason P
JP
Chua
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Ryosuke
R
Shimamura
Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA.
Lili
L
Zhao
Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Fan
F
Zhu
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Sriram
S
Venneti
Dulbecco Telethon Institute, Centre for Integrative Biology, University of Trento, Trento 38123, Italy.
Maria
M
Pennuto
Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Yuanfang
Y
Guan
Ionis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA.
Gene
G
Hung
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: liebermn@umich.edu.
Andrew P
AP
Lieberman
D000818:Animals; D050260:Carbohydrate Metabolism / Q000235:genetics; D002952:Citric Acid Cycle / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006019:Glycolysis / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D010805:Physical Conditioning, Animal; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism
C000607144:AR protein, mouse; D016376:Oligonucleotides, Antisense; D010455:Peptides; D011944:Receptors, Androgen; C097188:polyglutamine
CAG/polyglutamine disease; antisense oligonucleotides; exercise; glycolysis; metabolism; mitochondria; skeletal muscle; spinal and bulbar muscular atrophy
Hum Mol Genet. 2002 Aug 15;11(17):1967-76
12165558
PLoS One. 2013 Jul 23;8(7):e68078
23935853
Muscle Nerve. 2000 Jun;23(6):843-50
10842259
J Neurol Sci. 2008 Jan 15;264(1-2):100-5
17854832
Neurobiol Dis. 2009 Apr;34(1):113-20
19211034
Nucleic Acids Res. 1994 Aug 11;22(15):3181-6
8065934
Neurodegener Dis. 2005;2(3-4):202-7
16909026
J Neurosci. 2015 Apr 22;35(16):6444-51
25904795
Biochim Biophys Acta. 2009 Aug;1792(8):777-82
19447175
Neuron. 2002 Aug 29;35(5):855-64
12372281
J Clin Invest. 2006 Oct;116(10 ):2663-72
16981011
Hum Mol Genet. 1995 Apr;4(4):523-7
7633399
J Neurol Neurosurg Psychiatry. 2016 Aug;87(8):810-6
26503015
Diabetes. 2009 Dec;58(12):2788-96
19741162
Hum Mol Genet. 2014 Mar 1;23(5):1376-86
24150846
Bioinformatics. 2009 May 1;25(9):1105-11
19289445
PLoS Genet. 2011 Oct;7(10 ):e1002321
22022281
Brain. 2006 Jun;129(Pt 6):1446-55
16621916
Nat Biotechnol. 2013 Jan;31(1):46-53
23222703
Mol Endocrinol. 2010 Oct;24(10):1891-903
20392876
CNS Neurol Disord Drug Targets. 2013 Dec;12(8):1146-56
24040817
PLoS One. 2015 Feb 06;10(2):e0117232
25658945
Acta Neuropathol. 2016 Jul;132(1):127-44
26971100
Trends Endocrinol Metab. 2012 Sep;23 (9):451-8
22591987
J Mol Neurosci. 2016 Mar;58(3):388-93
26585990
J Clin Invest. 2015 Feb;125(2):831-45
25607844
Cell Rep. 2014 May 8;7(3):774-84
24746732
Neuron. 2009 Aug 13;63(3):316-28
19679072
J Biol Chem. 2005 Apr 1;280(13):12573-84
15640143
Am J Pathol. 2006 Jan;168(1):195-204
16400023
FEBS J. 2015 Feb;282(4):647-72
25495651
FASEB J. 2014 Jul;28(7):3211-24
24652947
Genome Biol. 2009;10(3):R25
19261174
Hum Mol Genet. 2011 Nov 15;20(22):4475-90
21873607
Brain. 2009 Dec;132(Pt 12):3242-51
19846582
Neuron. 2002 Aug 29;35(5):843-54
12372280
Nat Genet. 1993 Oct;5(2):184-8
8252045
Ann Clin Transl Neurol. 2015 Jul;2(7):739-47
26273686
EMBO Mol Med. 2015 Mar 27;7(5):526-46
25820275
Neuron. 2014 Apr 16;82(2):295-307
24742458
Diabetologia. 2010 Jun;53(6):1174-83
20217038
Cell. 2000 Dec 8;103(6):839-42
11136969
J Clin Invest. 2011 Mar;121(3):918-29
21393865
Mol Endocrinol. 2007 Sep;21(9):2152-63
17550977
Hum Mol Genet. 2009 Jan 1;18(1):27-42
18824496
Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18259-64
17984063
Physiol Genomics. 2001 Feb 07;5(1):45-52
11161005