Imperial College London

ProfessorSteveMarston

Faculty of MedicineNational Heart & Lung Institute

(Non-Clinical) Professor in Cardiovascular Biochemistry
 
 
 
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Contact

 

+44 (0)20 7594 2732s.marston Website

 
 
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Location

 

433ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Yuen:2015:hmg/ddv334,
author = {Yuen, M and Cooper, ST and Marston, SB and Nowak, KJ and McNamara, E and Mokbel, N and Ilkovski, B and Ravenscroft, G and Rendu, J and de, Winter JM and Klinge, L and Beggs, AH and North, KN and Ottenheijm, CA and Clarke, NF},
doi = {hmg/ddv334},
journal = {Human Molecular Genetics},
pages = {6278--6292},
title = {Muscle weakness in TPM3-myopathy is due to reduced Ca2+-sensitivity and impaired acto-myosin cross-bridge cycling in slow fibres.},
url = {http://dx.doi.org/10.1093/hmg/ddv334},
volume = {24},
year = {2015}
}

RIS format (EndNote, RefMan)

TY  - JOUR
AB - Dominant mutations in TPM3, encoding α-tropomyosinslow, cause a congenital myopathy characterised by generalised muscle weakness. Here, we used a multidisciplinary approach to investigate the mechanism of muscle dysfunction in twelve TPM3-myopathy patients.We confirm that slow myofibre hypotrophy is a diagnostic hallmark of TPM3-myopathy, and is commonly accompanied by skewing of fibre-type ratios (either slow or fast fibre predominance). Patient muscle contained normal ratios of the three tropomyosin isoforms and normal fibre-type expression of myosins and troponins. Using 2D-PAGE, we demonstrate that mutant α-tropomyosinslow was expressed, suggesting muscle dysfunction is due to a dominant-negative effect of mutant protein on muscle contraction. Molecular modelling suggested mutant α-tropomyosinslow likely impacts actin-tropomyosin interactions and, indeed, co-sedimentation assays showed reduced binding of mutant α-tropomyosinslow (R168C) to filamentous actin.Single fibre contractility studies of patient myofibres revealed marked slow myofibre specific abnormalities. At saturating [Ca(2+)] (pCa 4.5), patient slow fibres produced only 63% of the contractile force produced in control slow fibres and had reduced acto-myosin cross-bridge cycling kinetics. Importantly, due to reduced Ca(2+)-sensitivity, at sub-saturating [Ca(2+)] (pCa 6, levels typically released during in vivo contraction) patient slow fibres produced only 26% of the force generated by control slow fibres.Thus, weakness in TPM3-myopathy patients can be directly attributed to reduced slow fibre force at physiological [Ca(2+)], and impaired acto-myosin cross-bridge cycling kinetics. Fast myofibres are spared; however, they appear to be unable to compensate for slow fibre dysfunction. Abnormal Ca(2+)-sensitivity in TPM3-myopathy patients suggests Ca(2+)-sensitising drugs may represent a useful treatment for this condition.
AU - Yuen,M
AU - Cooper,ST
AU - Marston,SB
AU - Nowak,KJ
AU - McNamara,E
AU - Mokbel,N
AU - Ilkovski,B
AU - Ravenscroft,G
AU - Rendu,J
AU - de,Winter JM
AU - Klinge,L
AU - Beggs,AH
AU - North,KN
AU - Ottenheijm,CA
AU - Clarke,NF
DO - hmg/ddv334
EP - 6292
PY - 2015///
SN - 1460-2083
SP - 6278
TI - Muscle weakness in TPM3-myopathy is due to reduced Ca2+-sensitivity and impaired acto-myosin cross-bridge cycling in slow fibres.
T2 - Human Molecular Genetics
UR - http://dx.doi.org/10.1093/hmg/ddv334
UR - http://hdl.handle.net/10044/1/26673
VL - 24
ER -