Universität zu Köln

Mutsaers, Chantal A., Wishart, Thomas M., Lamont, Douglas J., Riessland, Markus ORCID: 0000-0003-2592-5045, Schreml, Julia, Comley, Laura H., Murray, Lyndsay M., Parson, Simon H., Lochmueller, Hanns, Wirth, Brunhilde ORCID: 0000-0003-4051-5191, Talbot, Kevin ORCID: 0000-0001-5490-1697 and Gillingwater, Thomas H. (2011). Reversible molecular pathology of skeletal muscle in spinal muscular atrophy. Hum. Mol. Genet., 20 (22). S. 4334 - 4345. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2083

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Abstract

Low levels of full-length survival motor neuron (SMN) protein cause the motor neuron disease, spinal muscular atrophy (SMA). Although motor neurons undoubtedly contribute directly to SMA pathogenesis, the role of muscle is less clear. We demonstrate significant disruption to the molecular composition of skeletal muscle in pre-symptomatic severe SMA mice, in the absence of any detectable degenerative changes in lower motor neurons and with a molecular profile distinct from that of denervated muscle. Functional cluster analysis of proteomic data and phospho-histone H2AX labelling of DNA damage revealed increased activity of cell death pathways in SMA muscle. Robust upregulation of voltage-dependent anion-selective channel protein 2 (Vdac2) and downregulation of parvalbumin in severe SMA mice was confirmed in a milder SMA mouse model and in human patient muscle biopsies. Molecular pathology of skeletal muscle was ameliorated in mice treated with the FDA-approved histone deacetylase inhibitor, suberoylanilide hydroxamic acid. We conclude that intrinsic pathology of skeletal muscle is an important and reversible event in SMA and also suggest that muscle proteins have the potential to act as novel biomarkers in SMA.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Mutsaers, Chantal A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wishart, Thomas M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lamont, Douglas J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Riessland, Markus UNSPECIFIED orcid.org/0000-0003-2592-5045 UNSPECIFIED Schreml, Julia UNSPECIFIED UNSPECIFIED UNSPECIFIED Comley, Laura H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Murray, Lyndsay M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Parson, Simon H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lochmueller, Hanns UNSPECIFIED UNSPECIFIED UNSPECIFIED Wirth, Brunhilde UNSPECIFIED orcid.org/0000-0003-4051-5191 UNSPECIFIED Talbot, Kevin UNSPECIFIED orcid.org/0000-0001-5490-1697 UNSPECIFIED Gillingwater, Thomas H. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-485383
DOI:	10.1093/hmg/ddr360
Journal or Publication Title:	Hum. Mol. Genet.
Volume:	20
Number:	22
Page Range:	S. 4334 - 4345
Date:	2011
Publisher:	OXFORD UNIV PRESS
Place of Publication:	OXFORD
ISSN:	1460-2083
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MOUSE MODELS; DIFFERENTIAL EXPRESSION; NEUROMUSCULAR-JUNCTION; MOTOR-NEURONS; SMN; APOPTOSIS; PROTEINS; DENERVATION; MICE; VULNERABILITY Multiple languages Biochemistry & Molecular Biology; Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/48538