Top

Published in:

Open Access 01-07-2016 | Original Paper

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

Authors: Anna Rocchi, Carmelo Milioto, Sara Parodi, Andrea Armirotti, Doriana Borgia, Matteo Pellegrini, Anna Urciuolo, Sibilla Molon, Valeria Morbidoni, Manuela Marabita, Vanina Romanello, Pamela Gatto, Bert Blaauw, Paolo Bonaldo, Fabio Sambataro, Diane M. Robins, Andrew P. Lieberman, Gianni Sorarù, Lodovica Vergani, Marco Sandri, Maria Pennuto

Published in: Acta Neuropathologica | Issue 1/2016

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.

Available only for authorised users

Abbott RA, Cox M, Markus H, Tomkins A (1992) Diet, body size and micronutrient status in Parkinson’s disease. Eur J Clin Nutr 46:879–884PubMed

Armirotti A, Basit A, Realini N, Caltagirone C, Bossu P, Spalletta G, Piomelli D (2014) Sample preparation and orthogonal chromatography for broad polarity range plasma metabolomics: application to human subjects with neurodegenerative dementia. Anal Biochem 455:48–54. doi:10.1016/j.ab.2014.03.019 CrossRefPubMed

Baskin KK, Winders BR, Olson EN (2015) Muscle as a “mediator” of systemic metabolism. Cell Metab 21:237–248. doi:10.1016/j.cmet.2014.12.021 CrossRefPubMedPubMedCentral

Bass A, Gutmann E, Hanzlikova V (1975) Biochemical and histochemical changes in energy supply enzyme pattern of muscles of the rat during old age. Gerontologia 21:31–45CrossRefPubMed

Basualto-Alarcon C, Jorquera G, Altamirano F, Jaimovich E, Estrada M (2013) Testosterone signals through mTOR and androgen receptor to induce muscle hypertrophy. Med Sci Sports Exerc 45:1712–1720. doi:10.1249/MSS.0b013e31828cf5f3 CrossRefPubMed

Bertaggia E, Scabia G, Dalise S, Lo Verso F, Santini F, Vitti P, Chisari C, Sandri M, Maffei M (2014) Haptoglobin is required to prevent oxidative stress and muscle atrophy. PLoS ONE 9:e100745. doi:10.1371/journal.pone.0100745 CrossRefPubMedPubMedCentral

Beyer PL, Palarino MY, Michalek D, Busenbark K, Koller WC (1995) Weight change and body composition in patients with Parkinson’s disease. J Am Diet Assoc 95:979–983. doi:10.1016/S0002-8223(95)00269-3

Blaauw B, Canato M, Agatea L, Toniolo L, Mammucari C, Masiero E, Abraham R, Sandri M, Schiaffino S, Reggiani C (2009) Inducible activation of Akt increases skeletal muscle mass and force without satellite cell activation. FASEB J 23:3896–3905. doi:10.1096/fj.09-131870

Block RC, Dorsey ER, Beck CA, Brenna JT, Shoulson I (2010) Altered cholesterol and fatty acid metabolism in Huntington disease. J Clin Lipidol 4:17–23. doi:10.1016/j.jacl.2009.11.003 CrossRefPubMedPubMedCentral

10.

Caccamo A, Majumder S, Richardson A, Strong R, Oddo S (2010) Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, and Tau: effects on cognitive impairments. J Biol Chem 285:13107–13120. doi:10.1074/jbc.M110.100420 CrossRefPubMedPubMedCentral

11.

Cai H, Cong WN, Ji S, Rothman S, Maudsley S, Martin B (2012) Metabolic dysfunction in Alzheimer’s disease and related neurodegenerative disorders. Curr Alzheimer Res 9:5–17. doi:10.2174/156720512799015064 CrossRefPubMedPubMedCentral

12.

Castets P, Lin S, Rion N, Di Fulvio S, Romanino K, Guridi M, Frank S, Tintignac LA, Sinnreich M, Ruegg MA (2013) Sustained activation of mTORC1 in skeletal muscle inhibits constitutive and starvation-induced autophagy and causes a severe, late-onset myopathy. Cell Metab 17:731–744. doi:10.1016/j.cmet.2013.03.015 CrossRefPubMed

13.

Chen W, Zhang X, Birsoy K, Roeder RG (2010) A muscle-specific knockout implicates nuclear receptor coactivator MED1 in the regulation of glucose and energy metabolism. Proc Natl Acad Sci USA 107:10196–10201. doi:10.1073/pnas.1005626107 CrossRefPubMedPubMedCentral

14.

Ching JK, Elizabeth SV, Ju JS, Lusk C, Pittman SK, Weihl CC (2013) mTOR dysfunction contributes to vacuolar pathology and weakness in valosin-containing protein associated inclusion body myopathy. Hum Mol Genet 22:1167–1179. doi:10.1093/hmg/dds524 CrossRefPubMed

15.

Chio A, Calvo A, Ilardi A, Cavallo E, Moglia C, Mutani R, Palmo A, Galletti R, Marinou K, Papetti L et al (2009) Lower serum lipid levels are related to respiratory impairment in patients with ALS. Neurology 73:1681–1685. doi:10.1212/WNL.0b013e3181c1df1e CrossRefPubMed

16.

Chua JP, Reddy SL, Merry DE, Adachi H, Katsuno M, Sobue G, Robins DM, Lieberman AP (2014) Transcriptional activation of TFEB/ZKSCAN3 target genes underlies enhanced autophagy in spinobulbar muscular atrophy. Hum Mol Genet 23:1376–1386. doi:10.1093/hmg/ddt527 CrossRefPubMed

17.

Cortes CJ, Ling SC, Guo LT, Hung G, Tsunemi T, Ly L, Tokunaga S, Lopez E, Sopher BL, Bennett CF et al (2014) Muscle expression of mutant androgen receptor accounts for systemic and motor neuron disease phenotypes in spinal and bulbar muscular atrophy. Neuron 82:295–307. doi:10.1016/j.neuron.2014.03.001 CrossRefPubMedPubMedCentral

18.

Cortes CJ, Miranda HC, Frankowski H, Batlevi Y, Young JE, Le A, Ivanov N, Sopher BL, Carromeu C, Muotri AR et al (2014) Polyglutamine-expanded androgen receptor interferes with TFEB to elicit autophagy defects in SBMA. Nat Neurosci 17:1180–1189. doi:10.1038/nn.3787 CrossRefPubMedPubMedCentral

19.

Crews L, Spencer B, Desplats P, Patrick C, Paulino A, Rockenstein E, Hansen L, Adame A, Galasko D, Masliah E (2010) Selective molecular alterations in the autophagy pathway in patients with Lewy body disease and in models of alpha-synucleinopathy. PLoS One 5:e9313. doi:10.1371/journal.pone.0009313

20.

Cunningham JT, Rodgers JT, Arlow DH, Vazquez F, Mootha VK, Puigserver P (2007) mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature 450:736–740 doi:10.1038/nature06322

21.

Da Cruz S, Parone PA, Lopes VS, Lillo C, McAlonis-Downes M, Lee SK, Vetto AP, Petrosyan S, Marsala M, Murphy AN et al (2012) Elevated PGC-1alpha activity sustains mitochondrial biogenesis and muscle function without extending survival in a mouse model of inherited ALS. Cell Metab 15:778–786. doi:10.1016/j.cmet.2012.03.019 CrossRefPubMedPubMedCentral

22.

Dehay B, Bove J, Rodriguez-Muela N, Perier C, Recasens A, Boya P, Vila M (2010) Pathogenic lysosomal depletion in Parkinson’s disease. J Neurosci 30:12535–12544. doi:10.1523/JNEUROSCI.1920-10.2010 CrossRefPubMed

23.

Dejager S, Bry-Gauillard H, Bruckert E, Eymard B, Salachas F, LeGuern E, Tardieu S, Chadarevian R, Giral P, Turpin G (2002) A comprehensive endocrine description of Kennedy’s disease revealing androgen insensitivity linked to CAG repeat length. J Clin Endocrinol Metab 87:3893–3901. doi:10.1210/jcem.87.8.8780 PubMed

24.

Demontis F, Perrimon N (2010) FOXO/4E-BP signaling in Drosophila muscles regulates organism-wide proteostasis during aging. Cell 143:813–825. doi:10.1016/j.cell.2010.10.007 CrossRefPubMedPubMedCentral

25.

Demontis F, Piccirillo R, Goldberg AL, Perrimon N (2013) The influence of skeletal muscle on systemic aging and lifespan. Aging Cell 12:943–949. doi:10.1111/acel.12126 CrossRefPubMed

26.

Dengler R, Konstanzer A, Kuther G, Hesse S, Wolf W, Struppler A (1990) Amyotrophic lateral sclerosis: macro-EMG and twitch forces of single motor units. Muscle Nerve 13:545–550. doi:10.1002/mus.880130612 CrossRefPubMed

27.

Desport JC, Preux PM, Truong TC, Vallat JM, Sautereau D, Couratier P (1999) Nutritional status is a prognostic factor for survival in ALS patients. Neurology 53:1059–1063CrossRefPubMed

28.

Desport JC, Torny F, Lacoste M, Preux PM, Couratier P (2005) Hypermetabolism in ALS: correlations with clinical and paraclinical parameters. Neurodegener Dis. 2:202–207. Doi:10.1159/000089626

29.

Di Paolo G, Kim TW (2011) Linking lipids to Alzheimer’s disease: cholesterol and beyond. Nat Rev Neurosci 12:284–296. doi:10.1038/nrn3012 CrossRefPubMedPubMedCentral

30.

Dibble CC, Manning BD (2013) Signal integration by mTORC1 coordinates nutrient input with biosynthetic output. Nat Cell Biol 15:555–564. doi:10.1038/ncb2763

31.

Dorst J, Cypionka J, Ludolph AC (2013) High-caloric food supplements in the treatment of amyotrophic lateral sclerosis: a prospective interventional study. Amyotroph Lateral Scler Frontotemporal Degener 14:533–536. doi:10.3109/21678421.2013.823999 CrossRefPubMed

32.

Dorst J, Kuhnlein P, Hendrich C, Kassubek J, Sperfeld AD, Ludolph AC (2011) Patients with elevated triglyceride and cholesterol serum levels have a prolonged survival in amyotrophic lateral sclerosis. J Neurol 258:613–617. doi:10.1007/s00415-010-5805-z CrossRefPubMed

33.

Dupuis L, Oudart H, Rene F, Gonzalez de Aguilar JL, Loeffler JP (2004) Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: benefit of a high-energy diet in a transgenic mouse model. Proc Natl Acad Sci USA 101:11159–11164. doi:10.1073/pnas.0402026101 CrossRefPubMedPubMedCentral

34.

Fernandez-Rhodes LE, Kokkinis AD, White MJ, Watts CA, Auh S, Jeffries NO, Shrader JA, Lehky TJ, Li L, Ryder JE et al (2011) Efficacy and safety of dutasteride in patients with spinal and bulbar muscular atrophy: a randomised placebo-controlled trial. Lancet Neurol 10:140–147. doi:10.1016/S1474-4422(10)70321-5 CrossRefPubMedPubMedCentral

35.

Fraulob JC, Ogg-Diamantino R, Fernandes-Santos C, Aguila MB, Mandarim-de-Lacerda CA (2010) A mouse model of metabolic syndrome: insulin resistance, fatty liver and non-alcoholic fatty pancreas disease (NAFPD) in C57BL/6 mice fed a high fat diet. J Clin Biochem Nutr 46:212–223. doi:10.3164/jcbn.09-83 CrossRefPubMedPubMedCentral

36.

Gallo V, Wark PA, Jenab M, Pearce N, Brayne C, Vermeulen R, Andersen PM, Hallmans G, Kyrozis A, Vanacore N et al (2013) Prediagnostic body fat and risk of death from amyotrophic lateral sclerosis: the EPIC cohort. Neurology 80:829–838. doi:10.1212/WNL.0b013e3182840689 CrossRefPubMedPubMedCentral

37.

Handschin C, Chin S, Li P, Liu F, Maratos-Flier E, Lebrasseur NK, Yan Z, Spiegelman BM (2007) Skeletal muscle fiber-type switching, exercise intolerance, and myopathy in PGC-1alpha muscle-specific knock-out animals. J Biol Chem 282:30014–30021. doi:10.1074/jbc.M704817200 CrossRefPubMed

38.

Harding AE, Thomas PK, Baraitser M, Bradbury PG, Morgan-Hughes JA, Ponsford JR (1982) X-linked recessive bulbospinal neuronopathy: a report of ten cases. J Neurol Neurosurg Psychiatry 45:1012–1019CrossRefPubMedPubMedCentral

39.

Holloszy JO, Chen M, Cartee GD, Young JC (1991) Skeletal muscle atrophy in old rats: differential changes in the three fiber types. Mech Ageing Dev 60:199–213. doi:10.1016/0047-6374(91)90131-I CrossRefPubMed

40.

Kemp MQ, Poort JL, Baqri RM, Lieberman AP, Breedlove SM, Miller KE, Jordan CL (2011) Impaired motoneuronal retrograde transport in two models of SBMA implicates two sites of androgen action. Hum Mol Genet 20:4475–4490. doi:10.1093/hmg/ddr380 CrossRefPubMedPubMedCentral

41.

Kennedy WR, Alter M, Sung JH (1968) Progressive proximal spinal and bulbar muscular atrophy of late onset. A sex-linked recessive trait. Neurology 18:671–680CrossRefPubMed

42.

Kornberg A (1955) Lactic dehydrogenase of muscle. In: Colowick SP, Kaplan NO (eds) Methods in enzymology. Academic Press, City

43.

La Spada AR, Wilson EM, Lubahn DB, Harding AE, Fischbeck KH (1991) Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352:77–79. doi:10.1038/352077a0 CrossRefPubMed

44.

Lee JH, Tecedor L, Chen YH, Monteys AM, Sowada MJ, Thompson LM, Davidson BL (2015) Reinstating aberrant mTORC1 activity in Huntington’s disease mice improves disease phenotypes. Neuron 85:303–315. doi:10.1016/j.neuron.2014.12.019 CrossRefPubMed

45.

Lieberman AP, Yu Z, Murray S, Peralta R, Low A, Guo S, Yu XX, Cortes CJ, Bennett CF, Monia BP et al (2014) Peripheral androgen receptor gene suppression rescues disease in mouse models of spinal and bulbar muscular atrophy. Cell Rep 7:774–784. doi:10.1016/j.celrep.2014.02.008 CrossRefPubMedPubMedCentral

46.

Lim WL, Martins IJ, Martins RN (2014) The involvement of lipids in Alzheimer’s disease. J Genet Genomics 41:261–274 doi:10.1016/j.jgg.2014.04.003

47.

Lin J, Wu H, Tarr PT, Zhang CY, Wu Z, Boss O, Michael LF, Puigserver P, Isotani E, Olson EN et al (2002) Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres. Nature 418:797–801. doi:10.1038/nature00904 CrossRefPubMed

48.

Lindauer E, Dupuis L, Muller HP, Neumann H, Ludolph AC, Kassubek J (2013) Adipose tissue distribution predicts survival in amyotrophic lateral sclerosis. PLoS ONE 8:e67783. doi:10.1371/journal.pone.0067783 CrossRefPubMedPubMedCentral

49.

Llewellyn KJ, Nalbandian A, Jung KM, Nguyen C, Avanesian A, Mozaffar T, Piomelli D, Kimonis VE (2014) Lipid-enriched diet rescues lethality and slows down progression in a murine model of VCP-associated disease. Hum Mol Genet. 23:1333–1344. doi:10.1093/hmg/ddt523

50.

MacLean HE, Chiu WS, Notini AJ, Axell AM, Davey RA, McManus JF, Ma C, Plant DR, Lynch GS, Zajac JD (2008) Impaired skeletal muscle development and function in male, but not female, genomic androgen receptor knockout mice. FASEB J 22:2676–2689. doi:10.1096/fj.08-105726 CrossRefPubMed

51.

Malagelada C, Jin ZH, Jackson-Lewis V, Przedborski S, Greene LA (2010) Rapamycin protects against neuron death in in vitro and in vivo models of Parkinson’s disease. J Neurosci 30:1166–1175. doi:10.1523/JNEUROSCI.3944-09.2010

52.

Malena A, Pennuto M, Tezze C, Querin G, D’Ascenzo C, Silani V, Cenacchi G, Scaramozza A, Romito S, Morandi L et al (2013) Androgen-dependent impairment of myogenesis in spinal and bulbar muscular atrophy. Acta Neuropathol 126:109–121. doi:10.1007/s00401-013-1122-9 CrossRefPubMed

53.

Mannaa M, Kramer S, Boschmann M, Gollasch M (2013) mTOR and regulation of energy homeostasis in humans. J Mol Med (Berl) 91:1167–1175. doi:10.1007/s00109-013-1057-6 CrossRef

54.

McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34:939–944CrossRefPubMed

55.

Menzies FM, Huebener J, Renna M, Bonin M, Riess O, Rubinsztein DC (2010) Autophagy induction reduces mutant ataxin-3 levels and toxicity in a mouse model of spinocerebellar ataxia type 3. Brain 133:93–104. doi:10.1093/brain/awp292 CrossRefPubMed

56.

Milan G, Romanello V, Pescatore F, Armani A, Paik JH, Frasson L, Seydel A, Zhao J, Abraham R, Goldberg AL et al (2015) Regulation of autophagy and the ubiquitin-proteasome system by the FoxO transcriptional network during muscle atrophy. Nat Commun 6:6670. doi:10.1038/ncomms7670 CrossRefPubMedPubMedCentral

57.

Mo K, Razak Z, Rao P, Yu Z, Adachi H, Katsuno M, Sobue G, Lieberman AP, Westwood JT, Monks DA (2010) Microarray analysis of gene expression by skeletal muscle of three mouse models of Kennedy disease/spinal bulbar muscular atrophy. PLoS One 5:e12922. doi:10.1371/journal.pone.0012922

58.

Mochel F, Charles P, Seguin F, Barritault J, Coussieu C, Perin L, Le Bouc Y, Gervais C, Carcelain G, Vassault A et al (2007) Early energy deficit in Huntington disease: identification of a plasma biomarker traceable during disease progression. PLoS ONE 2:e647. doi:10.1371/journal.pone.0000647 CrossRefPubMedPubMedCentral

59.

Monks DA, Johansen JA, Mo K, Rao P, Eagleson B, Yu Z, Lieberman AP, Breedlove SM, Jordan CL (2007) Overexpression of wild-type androgen receptor in muscle recapitulates polyglutamine disease. Proc Natl Acad Sci USA 104:18259–18264. doi:10.1073/pnas.0705501104

60.

Moon JS, Jin WJ, Kwak JH, Kim HJ, Yun MJ, Kim JW, Park SW, Kim KS (2011) Androgen stimulates glycolysis for de novo lipid synthesis by increasing the activities of hexokinase 2 and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 in prostate cancer cells. Biochem J 433:225–233. doi:10.1042/BJ20101104 CrossRefPubMed

61.

Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstrale M, Laurila E et al (2003) PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34:267–273. doi:10.1038/ng1180 CrossRefPubMed

62.

Moresi V, Carrer M, Grueter CE, Rifki OF, Shelton JM, Richardson JA, Bassel-Duby R, Olson EN (2012) Histone deacetylases 1 and 2 regulate autophagy flux and skeletal muscle homeostasis in mice. Proc Natl Acad Sci USA 109:1649–1654. doi:10.1073/pnas.1121159109

63.

Nedelsky NB, Pennuto M, Smith RB, Palazzolo I, Moore J, Nie Z, Neale G, Taylor JP (2010) Native functions of the androgen receptor are essential to pathogenesis in a Drosophila model of spinobulbar muscular atrophy. Neuron 67:936–952. doi:10.1016/j.neuron.2010.08.034

64.

Niederle B, Mayr R (1978) Course of denervation atrophy in type I and type II fibres of rat extensor digitorum longus muscle. Anat Embryol (Berl) 153:9–21CrossRef

65.

O’Reilly MW, House PJ, Tomlinson JW (2014) Understanding androgen action in adipose tissue. J Steroid Biochem Mol Biol 143:277–284. doi:10.1016/j.jsbmb.2014.04.008

66.

Okamoto K, Kihira T, Kondo T, Kobashi G, Washio M, Sasaki S, Yokoyama T, Miyake Y, Sakamoto N, Inaba Yet al (2007) Nutritional status and risk of amyotrophic lateral sclerosis in Japan. Amyotroph Lateral Scler 8:300–304. doi:10.1080/17482960701472249

67.

Orr HT, Zoghbi HY (2007) Trinucleotide repeat disorders. Annu Rev Neurosci 30:575–621. doi:10.1146/annurev.neuro.29.051605.113042 CrossRefPubMed

68.

Palamiuc L, Schlagowski A, Ngo ST, Vernay A, Dirrig-Grosch S, Henriques A, Boutillier AL, Zoll J, Echaniz-Laguna A, Loeffler JP et al (2015) A metabolic switch toward lipid use in glycolytic muscle is an early pathologic event in a mouse model of amyotrophic lateral sclerosis. EMBO Mol Med. doi:10.15252/emmm.201404433 PubMedPubMedCentral

69.

Palazzolo I, Burnett BG, Young JE, Brenne PL, La Spada AR, Fischbeck KH, Howell BW, Pennuto M (2007) Akt blocks ligand binding and protects against expanded polyglutamine androgen receptor toxicity. Hum Mol Genet 16:1593–1603. doi:10.1093/hmg/ddm109 CrossRefPubMed

70.

Palazzolo I, Stack C, Kong L, Musaro A, Adachi H, Katsuno M, Sobue G, Taylor JP, Sumner CJ, Fischbeck KH et al (2009) Overexpression of IGF-1 in muscle attenuates disease in a mouse model of spinal and bulbar muscular atrophy. Neuron 63:316–328. doi:10.1016/j.neuron.2009.07.019 CrossRefPubMedPubMedCentral

71.

Parodi S, Pennuto M (2011) Neurotoxic effects of androgens in spinal and bulbar muscular atrophy. Front Neuroendocrinol 32:416–425. doi:10.1016/j.yfrne.2011.06.003 CrossRefPubMed

72.

Pennuto M, Basso M (2015) In Vitro and In Vivo Modeling of Spinal and Bulbar Muscular Atrophy. J Mol Neurosci. doi:10.1007/s12031-015-0677-4

73.

Pratley RE, Salbe AD, Ravussin E, Caviness JN (2000) Higher sedentary energy expenditure in patients with Huntington’s disease. Ann Neurol 47:64–70CrossRefPubMed

74.

Pun S, Santos AF, Saxena S, Xu L, Caroni P (2006) Selective vulnerability and pruning of phasic motoneuron axons in motoneuron disease alleviated by CNTF. Nat Neurosci 9:408–419. doi:10.1038/nn1653

75.

Querin G, Bertolin C, Da Re E, Volpe M, Zara G, Pegoraro E, Caretta N, Foresta C, Silvano M, Corrado D et al (2015) Non-neural phenotype of spinal and bulbar muscular atrophy: results from a large cohort of Italian patients. J Neurol Neurosurg Psychiatry. doi:10.1136/jnnp-2015-311305

76.

Quiat D, Voelker KA, Pei J, Grishin NV, Grange RW, Bassel-Duby R, Olson EN (2011) Concerted regulation of myofiber-specific gene expression and muscle performance by the transcriptional repressor Sox6. Proc Natl Acad Sci U S A 108:10196–10201. doi:10.1073/pnas.1107413108 CrossRefPubMedPubMedCentral

77.

Ramzan F, McPhail M, Rao P, Mo K, Halievski K, Swift-Gallant A, Mendoza-Viveros L, Cheng HY, Monks DA (2015) Distinct etiological roles for myocytes and motor neurons in a mouse model of Kennedy’s disease/spinobulbar muscular atrophy. J Neurosci 35:6444–6451. doi:10.1523/JNEUROSCI.3599-14.2015 CrossRefPubMed

78.

Rana K, Davey RA, Zajac JD (2014) Human androgen deficiency: insights gained from androgen receptor knockout mouse models. Asian J Androl 16:169–177. doi:10.4103/1008-682X.122590 CrossRefPubMedPubMedCentral

79.

Ranganathan S, Harmison GG, Meyertholen K, Pennuto M, Burnett BG, Fischbeck KH (2009) Mitochondrial abnormalities in spinal and bulbar muscular atrophy. Hum Mol Genet 18:27–42. doi:10.1093/hmg/ddn310 CrossRefPubMed

80.

Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, Scaravilli F, Easton DF, Duden R, O’Kane CJ et al (2004) Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 36:585–595. doi:10.1038/ng1362 CrossRefPubMed

81.

Rocchi A, Pennuto M (2013) New routes to therapy for spinal and bulbar muscular atrophy. J Mol Neurosci 50:514–523. doi:10.1007/s12031-013-9978-7 CrossRefPubMed

82.

Romanello V, Guadagnin E, Gomes L, Roder I, Sandri C, Petersen Y, Milan G, Masiero E, Del Piccolo P, Foretz M et al (2010) Mitochondrial fission and remodelling contributes to muscle atrophy. EMBO J 29:1774–1785. doi:10.1038/emboj.2010.60 CrossRefPubMedPubMedCentral

83.

Rusmini P, Polanco MJ, Cristofani R, Cicardi ME, Meroni M, Galbiati M, Piccolella M, Messi E, Giorgetti E, Lieberman AP et al (2015) Aberrant autophagic response in the muscle of a knock-in mouse model of spinal and bulbar muscular atrophy. Sci Rep 5:15174. doi:10.1038/srep15174 CrossRefPubMedPubMedCentral

84.

Sambataro F, Pennuto M (2012) Cell-autonomous and non-cell-autonomous toxicity in polyglutamine diseases. Prog Neurobiol 97:152–172. doi:10.1016/j.pneurobio.2011.10.003 CrossRefPubMed

85.

Sanberg PR, Fibiger HC, Mark RF (1981) Body weight and dietary factors in Huntington’s disease patients compared with matched controls. Med J Aust 1:407–409PubMed

86.

Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, Markhard AL, Sabatini DM (2006) Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22:159–168. doi:10.1016/j.molcel.2006.03.029 CrossRefPubMed

87.

Sardiello M, Palmieri M, di Ronza A, Medina DL, Valenza M, Gennarino VA, Di Malta C, Donaudy F, Embrione V, Polishchuk RS et al (2009) A gene network regulating lysosomal biogenesis and function. Science 325:473–477. doi:10.1126/science.1174447 PubMed

88.

Sartori R, Schirwis E, Blaauw B, Bortolanza S, Zhao J, Enzo E, Stantzou A, Mouisel E, Toniolo L, Ferry A et al (2013) BMP signaling controls muscle mass. Nat Genet 45:1309–1318. doi:10.1038/ng.2772 CrossRefPubMed

89.

Scaramuzzino C, Casci I, Parodi S, Lievens PM, Polanco MJ, Milioto C, Chivet M, Monaghan J, Mishra A, Badders N et al (2015) Protein arginine methyltransferase 6 enhances polyglutamine-expanded androgen receptor function and toxicity in spinal and bulbar muscular atrophy. Neuron 85:88–100. doi:10.1016/j.neuron.2014.12.031 CrossRefPubMedPubMedCentral

90.

Scherz-Shouval R, Elazar Z (2007) ROS, mitochondria and the regulation of autophagy. Trends Cell Biol 17:422–427. doi:10.1016/j.tcb.2007.07.009 CrossRefPubMed

91.

Schiaffino S, Dyar KA, Ciciliot S, Blaauw B, Sandri M (2013) Mechanisms regulating skeletal muscle growth and atrophy. FEBS J 280:4294–4314. doi:10.1111/febs.12253 CrossRefPubMed

92.

Schmidt EK, Clavarino G, Ceppi M, Pierre P (2009) SUnSET, a nonradioactive method to monitor protein synthesis. Nat Methods 6:275–277. doi:10.1038/nmeth.1314 CrossRefPubMed

93.

Seth A, Steel JH, Nichol D, Pocock V, Kumaran MK, Fritah A, Mobberley M, Ryder TA, Rowlerson A, Scott J et al (2007) The transcriptional corepressor RIP140 regulates oxidative metabolism in skeletal muscle. Cell Metab 6:236–245. doi:10.1016/j.cmet.2007.08.004 CrossRefPubMedPubMedCentral

94.

Settembre C, Zoncu R, Medina DL, Vetrini F, Erdin S, Huynh T, Ferron M, Karsenty G, Vellard MC, Facchinetti V et al (2012) A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J 31:1095–1108. doi:10.1038/emboj.2012.32 CrossRefPubMedPubMedCentral

95.

She P, Zhang Z, Marchionini D, Diaz WC, Jetton TJ, Kimball SR, Vary TC, Lang CH, Lynch CJ (2011) Molecular characterization of skeletal muscle atrophy in the R6/2 mouse model of Huntington’s disease. Am J Physiol Endocrinol Metab 301:E49–E61. doi:10.1152/ajpendo.00630.2010 CrossRefPubMedPubMedCentral

96.

Soraru G, D’Ascenzo C, Polo A, Palmieri A, Baggio L, Vergani L, Gellera C, Moretto G, Pegoraro E, Angelini C (2008) Spinal and bulbar muscular atrophy: skeletal muscle pathology in male patients and heterozygous females. J Neurol Sci 264:100–105. doi:10.1016/j.jns.2007.08.012 CrossRefPubMed

97.

Sparks LM, Xie H, Koza RA, Mynatt R, Hulver MW, Bray GA, Smith SR (2005) A high-fat diet coordinately downregulates genes required for mitochondrial oxidative phosphorylation in skeletal muscle. Diabetes 54:1926–1933. doi:10.2337/diabetes.54.7.1926 CrossRefPubMed

98.

Spilman P, Podlutskaya N, Hart MJ, Debnath J, Gorostiza O, Bredesen D, Richardson A, Strong R, Galvan V (2010) Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer’s disease. PLoS ONE 5:e9979. doi:10.1371/journal.pone.0009979 CrossRefPubMedPubMedCentral

99.

Spinazzi M, Casarin A, Pertegato V, Salviati L, Angelini C (2012) Assessment of mitochondrial respiratory chain enzymatic activities on tissues and cultured cells. Nat Protoc 7:1235–1246. doi:10.1038/nprot.2012.058

100.

Tisdale MJ (2009) Mechanisms of cancer cachexia. Physiol Rev 89:381–410. doi:10.1152/physrev.00016.2008 CrossRefPubMed

101.

Trejo A, Boll MC, Alonso ME, Ochoa A, Velasquez L (2005) Use of oral nutritional supplements in patients with Huntington’s disease. Nutrition 21:889–894. doi:10.1016/j.nut.2004.12.012 CrossRefPubMed

102.

Wang IF, Guo BS, Liu YC, Wu CC, Yang CH, Tsai KJ, Shen CK (2012) Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43. Proc Natl Acad Sci USA 109:15024–15029. doi:10.1073/pnas.1206362109 CrossRefPubMedPubMedCentral

103.

Wills AM, Hubbard J, Macklin EA, Glass J, Tandan R, Simpson EP, Brooks B, Gelinas D, Mitsumoto H, Mozaffar T et al (2014) Hypercaloric enteral nutrition in patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet 383:2065–2072. doi:10.1016/S0140-6736(14)60222-1 CrossRefPubMedPubMedCentral

104.

Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, Troy A, Cinti S, Lowell B, Scarpulla RC et al (1999) Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell 98:115–124. doi:10.1016/S0092-8674(00)80611-X CrossRefPubMed

105.

Yang JW, Kim SM, Kim HJ, Kim JE, Park KS, Kim SH, Lee KW, Sung JJ (2013) Hypolipidemia in patients with amyotrophic lateral sclerosis: a possible gender difference? J Clin Neurol 9:125–129. doi:10.3988/jcn.2013.9.2.125 CrossRefPubMedPubMedCentral

106.

Yu Z, Dadgar N, Albertelli M, Gruis K, Jordan C, Robins DM, Lieberman AP (2006) Androgen-dependent pathology demonstrates myopathic contribution to the Kennedy disease phenotype in a mouse knock-in model. J Clin Invest 116:2663–2672. doi:10.1172/JCI28773 CrossRefPubMedPubMedCentral

107.

Yu Z, Dadgar N, Albertelli M, Scheller A, Albin RL, Robins DM, Lieberman AP (2006) Abnormalities of germ cell maturation and sertoli cell cytoskeleton in androgen receptor 113 CAG knock-in mice reveal toxic effects of the mutant protein. Am J Pathol 168:195–204. doi:10.2353/ajpath.2006.050619 CrossRefPubMedPubMedCentral

108.

Yu Z, Wang AM, Adachi H, Katsuno M, Sobue G, Yue Z, Robins DM, Lieberman AP (2011) Macroautophagy is regulated by the UPR-mediator CHOP and accentuates the phenotype of SBMA mice. PLoS Genet 7:e1002321. doi:10.1371/journal.pgen.1002321 CrossRefPubMedPubMedCentral

109.

Zhang X, Li L, Chen S, Yang D, Wang Y, Wang Z, Le W (2011) Rapamycin treatment augments motor neuron degeneration in SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Autophagy 7:412–425 (pii:14541) CrossRefPubMed

Title: Glycolytic-to-oxidative fiber-type switch and mTOR signaling activation are early-onset features of SBMA muscle modified by high-fat diet
Authors: Anna Rocchi
Carmelo Milioto
Sara Parodi
Andrea Armirotti
Doriana Borgia
Matteo Pellegrini
Anna Urciuolo
Sibilla Molon
Valeria Morbidoni
Manuela Marabita
Vanina Romanello
Pamela Gatto
Bert Blaauw
Paolo Bonaldo
Fabio Sambataro
Diane M. Robins
Andrew P. Lieberman
Gianni Sorarù
Lodovica Vergani
Marco Sandri
Maria Pennuto
Publication date: 01-07-2016
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 1/2016
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-016-1550-4

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

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

Abstract

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2016

ECEL1 mutation implicates impaired axonal arborization of motor nerves in the pathogenesis of distal arthrogryposis

The role of glial-specific Kir4.1 in normal and pathological states of the CNS

α-Synuclein-induced myelination deficit defines a novel interventional target for multiple system atrophy

Neurofilament depletion improves microtubule dynamics via modulation of Stat3/stathmin signaling

NG2, a common denominator for neuroinflammation, blood–brain barrier alteration, and oligodendrocyte precursor response in EAE, plays a role in dendritic cell activation

Poorly differentiated chordoma with SMARCB1/INI1 loss: a distinct molecular entity with dismal prognosis