Skip to main content
Top
Published in: Clinical and Translational Medicine 1/2015

Open Access 01-12-2015 | Commentary

A shared mechanism of muscle wasting in cancer and Huntington’s disease

Authors: Michal Mielcarek, Mark Isalan

Published in: Clinical and Translational Medicine | Issue 1/2015

Login to get access

Abstract

Skeletal muscle loss and dysfunction in aging and chronic diseases is one of the major causes of mortality in patients, and is relevant for a wide variety of diseases such as neurodegeneration and cancer. Muscle loss is accompanied by changes in gene expression and metabolism that lead to contractile impairment and likely affect whole-body metabolism and function. The changes may be caused by inactivity, inflammation, age-related factors or unbalanced nutrition. Although links with skeletal muscle loss have been found in diseases with disparate aetiologies, for example both in Huntington’s disease (HD) and cancer cachexia, the outcome is a similar impairment and mortality. This short commentary aims to summarize recent achievements in the identification of common mechanisms leading to the skeletal muscle wasting syndrome seen in diseases as different as cancer and HD. The latter is the most common hereditary neurodegenerative disorder and muscle wasting is an important component of its pathology. In addition, possible therapeutic strategies for anti-cachectic treatment will be also discussed in the light of their translation into possible therapeutic approaches for HD.
Literature
2.
go back to reference Zielonka D, Mielcarek M, Landwehrmeyer GB (2015) Update on Huntington’s disease: advances in care and emerging therapeutic options. Parkinsonism Relat Disord 21(3):169–178CrossRefPubMed Zielonka D, Mielcarek M, Landwehrmeyer GB (2015) Update on Huntington’s disease: advances in care and emerging therapeutic options. Parkinsonism Relat Disord 21(3):169–178CrossRefPubMed
3.
go back to reference Gutekunst CA, Li SH, Yi H, Mulroy JS, Kuemmerle S, Jones R et al (1999) Nuclear and neuropil aggregates in Huntington’s disease: relationship to neuropathology. J Neurosci 19(7):2522–2534PubMed Gutekunst CA, Li SH, Yi H, Mulroy JS, Kuemmerle S, Jones R et al (1999) Nuclear and neuropil aggregates in Huntington’s disease: relationship to neuropathology. J Neurosci 19(7):2522–2534PubMed
4.
go back to reference Mielcarek M, Inuabasi L, Bondulich MK, Muller T, Osborne GF, Franklin SA et al (2014) Dysfunction of the CNS–heart axis in mouse models of Huntington’s disease. PLoS Genet 10(8):e1004550PubMedCentralCrossRefPubMed Mielcarek M, Inuabasi L, Bondulich MK, Muller T, Osborne GF, Franklin SA et al (2014) Dysfunction of the CNS–heart axis in mouse models of Huntington’s disease. PLoS Genet 10(8):e1004550PubMedCentralCrossRefPubMed
5.
go back to reference Mielcarek M, Bondulich MK, Inuabasi L, Franklin SA, Muller T, Bates GP (2014) The Huntington’s disease-related cardiomyopathy prevents a hypertrophic response in the R6/2 mouse model. PLoS One 9(9):e108961PubMedCentralCrossRefPubMed Mielcarek M, Bondulich MK, Inuabasi L, Franklin SA, Muller T, Bates GP (2014) The Huntington’s disease-related cardiomyopathy prevents a hypertrophic response in the R6/2 mouse model. PLoS One 9(9):e108961PubMedCentralCrossRefPubMed
6.
go back to reference Zielonka D, Piotrowska I, Mielcarek M (2014) Cardiac dysfunction in Huntington’s disease. Exp Clin Cardiol 20:2547–2554 Zielonka D, Piotrowska I, Mielcarek M (2014) Cardiac dysfunction in Huntington’s disease. Exp Clin Cardiol 20:2547–2554
8.
go back to reference Huang S, Yang S, Guo J, Yan S, Gaertig MA, Li S et al (2015) Large polyglutamine repeats cause muscle degeneration in SCA17 mice. Cell Rep 13(1):196–208CrossRefPubMed Huang S, Yang S, Guo J, Yan S, Gaertig MA, Li S et al (2015) Large polyglutamine repeats cause muscle degeneration in SCA17 mice. Cell Rep 13(1):196–208CrossRefPubMed
9.
go back to reference Boyle PA, Buchman AS, Wilson RS, Leurgans SE, Bennett DA (2009) Association of muscle strength with the risk of Alzheimer disease and the rate of cognitive decline in community-dwelling older persons. Arch Neurol 66(11):1339–1344PubMedCentralCrossRefPubMed Boyle PA, Buchman AS, Wilson RS, Leurgans SE, Bennett DA (2009) Association of muscle strength with the risk of Alzheimer disease and the rate of cognitive decline in community-dwelling older persons. Arch Neurol 66(11):1339–1344PubMedCentralCrossRefPubMed
10.
go back to reference Springer J, Schust S, Peske K, Tschirner A, Rex A, Engel O et al (2014) Catabolic signaling and muscle wasting after acute ischemic stroke in mice: indication for a stroke-specific sarcopenia. Stroke 45(12):3675–3683CrossRefPubMed Springer J, Schust S, Peske K, Tschirner A, Rex A, Engel O et al (2014) Catabolic signaling and muscle wasting after acute ischemic stroke in mice: indication for a stroke-specific sarcopenia. Stroke 45(12):3675–3683CrossRefPubMed
11.
go back to reference Mielcarek M, Toczek M, Smeets CJ, Franklin SA, Bondulich MK, Jolinon N et al (2015) HDAC4–myogenin axis as an important marker of HD-related skeletal muscle atrophy. PLoS Genet 11(3):e1005021PubMedCentralCrossRefPubMed Mielcarek M, Toczek M, Smeets CJ, Franklin SA, Bondulich MK, Jolinon N et al (2015) HDAC4–myogenin axis as an important marker of HD-related skeletal muscle atrophy. PLoS Genet 11(3):e1005021PubMedCentralCrossRefPubMed
12.
go back to reference Aulino P, Berardi E, Cardillo VM, Rizzuto E, Perniconi B, Ramina C et al (2010) Molecular, cellular and physiological characterization of the cancer cachexia-inducing C26 colon carcinoma in mouse. BMC Cancer 10:363PubMedCentralCrossRefPubMed Aulino P, Berardi E, Cardillo VM, Rizzuto E, Perniconi B, Ramina C et al (2010) Molecular, cellular and physiological characterization of the cancer cachexia-inducing C26 colon carcinoma in mouse. BMC Cancer 10:363PubMedCentralCrossRefPubMed
13.
go back to reference Murphy KT, Chee A, Trieu J, Naim T, Lynch GS (2012) Importance of functional and metabolic impairments in the characterization of the C-26 murine model of cancer cachexia. Dis Model Mech 5(4):533–545PubMedCentralCrossRefPubMed Murphy KT, Chee A, Trieu J, Naim T, Lynch GS (2012) Importance of functional and metabolic impairments in the characterization of the C-26 murine model of cancer cachexia. Dis Model Mech 5(4):533–545PubMedCentralCrossRefPubMed
15.
go back to reference Magnusson-Lind A, Davidsson M, Silajdzic E, Hansen C, McCourt AC, Tabrizi SJ et al (2014) Skeletal muscle atrophy in R6/2 mice—altered circulating skeletal muscle markers and gene expression profile changes. J Huntingtons Dis 3(1):13–24PubMed Magnusson-Lind A, Davidsson M, Silajdzic E, Hansen C, McCourt AC, Tabrizi SJ et al (2014) Skeletal muscle atrophy in R6/2 mice—altered circulating skeletal muscle markers and gene expression profile changes. J Huntingtons Dis 3(1):13–24PubMed
16.
go back to reference Antunes D, Padrao AI, Maciel E, Santinha D, Oliveira P, Vitorino R et al (2014) Molecular insights into mitochondrial dysfunction in cancer-related muscle wasting. Biochim Biophys Acta 1841(6):896–905CrossRefPubMed Antunes D, Padrao AI, Maciel E, Santinha D, Oliveira P, Vitorino R et al (2014) Molecular insights into mitochondrial dysfunction in cancer-related muscle wasting. Biochim Biophys Acta 1841(6):896–905CrossRefPubMed
17.
go back to reference Constantinou C, Fontes de Oliveira CC, Mintzopoulos D, Busquets S, He J, Kesarwani M et al (2011) Nuclear magnetic resonance in conjunction with functional genomics suggests mitochondrial dysfunction in a murine model of cancer cachexia. Int J Mol Med 27(1):15–24PubMedCentralPubMed Constantinou C, Fontes de Oliveira CC, Mintzopoulos D, Busquets S, He J, Kesarwani M et al (2011) Nuclear magnetic resonance in conjunction with functional genomics suggests mitochondrial dysfunction in a murine model of cancer cachexia. Int J Mol Med 27(1):15–24PubMedCentralPubMed
18.
go back to reference Williams AH, Valdez G, Moresi V, Qi X, McAnally J, Elliott JL et al (2009) MicroRNA-206 delays ALS progression and promotes regeneration of neuromuscular synapses in mice. Science 326(5959):1549–1554PubMedCentralCrossRefPubMed Williams AH, Valdez G, Moresi V, Qi X, McAnally J, Elliott JL et al (2009) MicroRNA-206 delays ALS progression and promotes regeneration of neuromuscular synapses in mice. Science 326(5959):1549–1554PubMedCentralCrossRefPubMed
19.
go back to reference Bruneteau G, Simonet T, Bauche S, Mandjee N, Malfatti E, Girard E et al (2013) Muscle histone deacetylase 4 upregulation in amyotrophic lateral sclerosis: potential role in reinnervation ability and disease progression. Brain 136(Pt 8):2359–2368CrossRefPubMed Bruneteau G, Simonet T, Bauche S, Mandjee N, Malfatti E, Girard E et al (2013) Muscle histone deacetylase 4 upregulation in amyotrophic lateral sclerosis: potential role in reinnervation ability and disease progression. Brain 136(Pt 8):2359–2368CrossRefPubMed
20.
go back to reference Bricceno KV, Sampognaro PJ, Van Meerbeke JP, Sumner CJ, Fischbeck KH, Burnett BG (2012) Histone deacetylase inhibition suppresses myogenin-dependent atrogene activation in spinal muscular atrophy mice. Hum Mol Genet 21(20):4448–4459PubMedCentralCrossRefPubMed Bricceno KV, Sampognaro PJ, Van Meerbeke JP, Sumner CJ, Fischbeck KH, Burnett BG (2012) Histone deacetylase inhibition suppresses myogenin-dependent atrogene activation in spinal muscular atrophy mice. Hum Mol Genet 21(20):4448–4459PubMedCentralCrossRefPubMed
21.
go back to reference Mielcarek M, Landles C, Weiss A, Bradaia A, Seredenina T, Inuabasi L et al (2013) HDAC4 reduction: a novel therapeutic strategy to target cytoplasmic huntingtin and ameliorate neurodegeneration. PLoS Biol 11(11):e1001717PubMedCentralCrossRefPubMed Mielcarek M, Landles C, Weiss A, Bradaia A, Seredenina T, Inuabasi L et al (2013) HDAC4 reduction: a novel therapeutic strategy to target cytoplasmic huntingtin and ameliorate neurodegeneration. PLoS Biol 11(11):e1001717PubMedCentralCrossRefPubMed
22.
go back to reference Mielcarek M, Benn CL, Franklin SA, Smith DL, Woodman B, Marks PA et al (2011) SAHA decreases HDAC 2 and 4 levels in vivo and improves molecular phenotypes in the R6/2 mouse model of Huntington’s disease. PLoS One 6(11):e27746PubMedCentralCrossRefPubMed Mielcarek M, Benn CL, Franklin SA, Smith DL, Woodman B, Marks PA et al (2011) SAHA decreases HDAC 2 and 4 levels in vivo and improves molecular phenotypes in the R6/2 mouse model of Huntington’s disease. PLoS One 6(11):e27746PubMedCentralCrossRefPubMed
23.
go back to reference Mielcarek M, Zielonka D, Carnemolla A, Marcinkowski JT, Guidez F (2015) HDAC4 as a potential therapeutic target in neurodegenerative diseases: a summary of recent achievements. Front Cell Neurosci 9:42PubMedCentralCrossRefPubMed Mielcarek M, Zielonka D, Carnemolla A, Marcinkowski JT, Guidez F (2015) HDAC4 as a potential therapeutic target in neurodegenerative diseases: a summary of recent achievements. Front Cell Neurosci 9:42PubMedCentralCrossRefPubMed
24.
go back to reference Choi MC, Ryu S, Hao R, Wang B, Kapur M, Fan CM et al (2014) HDAC4 promotes Pax7-dependent satellite cell activation and muscle regeneration. EMBO Rep 15(11):1175–1183PubMedCentralCrossRefPubMed Choi MC, Ryu S, Hao R, Wang B, Kapur M, Fan CM et al (2014) HDAC4 promotes Pax7-dependent satellite cell activation and muscle regeneration. EMBO Rep 15(11):1175–1183PubMedCentralCrossRefPubMed
25.
go back to reference He WA, Berardi E, Cardillo VM, Acharyya S, Aulino P, Thomas-Ahner J et al (2013) NF-kappaB-mediated Pax7 dysregulation in the muscle microenvironment promotes cancer cachexia. J Clin Invest 123(11):4821–4835PubMedCentralCrossRefPubMed He WA, Berardi E, Cardillo VM, Acharyya S, Aulino P, Thomas-Ahner J et al (2013) NF-kappaB-mediated Pax7 dysregulation in the muscle microenvironment promotes cancer cachexia. J Clin Invest 123(11):4821–4835PubMedCentralCrossRefPubMed
26.
go back to reference Inui A (1999) Cancer anorexia-cachexia syndrome: are neuropeptides the key? Cancer Res 59(18):4493–4501PubMed Inui A (1999) Cancer anorexia-cachexia syndrome: are neuropeptides the key? Cancer Res 59(18):4493–4501PubMed
27.
go back to reference Braun TP, Zhu X, Szumowski M, Scott GD, Grossberg AJ, Levasseur PR et al (2011) Central nervous system inflammation induces muscle atrophy via activation of the hypothalamic-pituitary-adrenal axis. J Exp Med 208(12):2449–2463PubMedCentralCrossRefPubMed Braun TP, Zhu X, Szumowski M, Scott GD, Grossberg AJ, Levasseur PR et al (2011) Central nervous system inflammation induces muscle atrophy via activation of the hypothalamic-pituitary-adrenal axis. J Exp Med 208(12):2449–2463PubMedCentralCrossRefPubMed
28.
go back to reference Chen JL, Walton KL, Winbanks CE, Murphy KT, Thomson RE, Makanji Y et al (2014) Elevated expression of activins promotes muscle wasting and cachexia. FASEB J 28(4):1711–1723CrossRefPubMed Chen JL, Walton KL, Winbanks CE, Murphy KT, Thomson RE, Makanji Y et al (2014) Elevated expression of activins promotes muscle wasting and cachexia. FASEB J 28(4):1711–1723CrossRefPubMed
29.
go back to reference Lokireddy S, Wijesoma IW, Teng S, Bonala S, Gluckman PD, McFarlane C et al (2012) The ubiquitin ligase Mul1 induces mitophagy in skeletal muscle in response to muscle-wasting stimuli. Cell Metab 16(5):613–624CrossRefPubMed Lokireddy S, Wijesoma IW, Teng S, Bonala S, Gluckman PD, McFarlane C et al (2012) The ubiquitin ligase Mul1 induces mitophagy in skeletal muscle in response to muscle-wasting stimuli. Cell Metab 16(5):613–624CrossRefPubMed
30.
go back to reference Zhou X, Wang JL, Lu J, Song Y, Kwak KS, Jiao Q et al (2010) Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival. Cell 142(4):531–543CrossRefPubMed Zhou X, Wang JL, Lu J, Song Y, Kwak KS, Jiao Q et al (2010) Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival. Cell 142(4):531–543CrossRefPubMed
31.
go back to reference Silva KA, Dong J, Dong Y, Dong Y, Schor N, Tweardy DJ et al (2015) Inhibition of Stat3 activation suppresses caspase-3 and the ubiquitin-proteasome system, leading to preservation of muscle mass in cancer cachexia. J Biol Chem 290(17):11177–11187CrossRefPubMed Silva KA, Dong J, Dong Y, Dong Y, Schor N, Tweardy DJ et al (2015) Inhibition of Stat3 activation suppresses caspase-3 and the ubiquitin-proteasome system, leading to preservation of muscle mass in cancer cachexia. J Biol Chem 290(17):11177–11187CrossRefPubMed
32.
go back to reference Kamei Y, Miura S, Suzuki M, Kai Y, Mizukami J, Taniguchi T et al (2004) Skeletal muscle FOXO1 (FKHR) transgenic mice have less skeletal muscle mass, down-regulated Type I (slow twitch/red muscle) fiber genes, and impaired glycemic control. J Biol Chem 279(39):41114–41123CrossRefPubMed Kamei Y, Miura S, Suzuki M, Kai Y, Mizukami J, Taniguchi T et al (2004) Skeletal muscle FOXO1 (FKHR) transgenic mice have less skeletal muscle mass, down-regulated Type I (slow twitch/red muscle) fiber genes, and impaired glycemic control. J Biol Chem 279(39):41114–41123CrossRefPubMed
33.
go back to reference Reed SA, Sandesara PB, Senf SM, Judge AR (2012) Inhibition of FoxO transcriptional activity prevents muscle fiber atrophy during cachexia and induces hypertrophy. FASEB J 26(3):987–1000PubMedCentralCrossRefPubMed Reed SA, Sandesara PB, Senf SM, Judge AR (2012) Inhibition of FoxO transcriptional activity prevents muscle fiber atrophy during cachexia and induces hypertrophy. FASEB J 26(3):987–1000PubMedCentralCrossRefPubMed
34.
go back to reference Su J, Ekman C, Oskolkov N, Lahti L, Strom K, Brazma A et al (2015) A novel atlas of gene expression in human skeletal muscle reveals molecular changes associated with aging. Skelet Muscle 5:35PubMedCentralCrossRefPubMed Su J, Ekman C, Oskolkov N, Lahti L, Strom K, Brazma A et al (2015) A novel atlas of gene expression in human skeletal muscle reveals molecular changes associated with aging. Skelet Muscle 5:35PubMedCentralCrossRefPubMed
Metadata
Title
A shared mechanism of muscle wasting in cancer and Huntington’s disease
Authors
Michal Mielcarek
Mark Isalan
Publication date
01-12-2015
Publisher
Springer Berlin Heidelberg
Published in
Clinical and Translational Medicine / Issue 1/2015
Electronic ISSN: 2001-1326
DOI
https://doi.org/10.1186/s40169-015-0076-z

Other articles of this Issue 1/2015

Clinical and Translational Medicine 1/2015 Go to the issue