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This Article Full Text Full Text (PDF) All Versions of this Article: 586/12/2993    most recent jphysiol.2008.153650v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Ochala, J. Articles by Larsson, L. PubMed PubMed Citation Articles by Ochala, J. Articles by Larsson, L. Related Collections Skeletal Muscle and Exercise Related Article

¹ Department of Clinical Neurophysiology, Uppsala University Hospital, Uppsala, Sweden
² Department of Pathology, Sahlgrenska University Hospital, Göteborg, Göteborg, Sweden
³ Center for Development and Health Genetics, the Pennsylvania State University, University Park, USA

A novel E41K β-tropomyosin (β-Tm) mutation, associated with congenital myopathy and muscle weakness, was recently identified in a woman and her daughter. In both patients, muscle weakness was coupled with muscle fibre atrophy. It remains unknown, however, whether the E41K β-Tm mutation directly affects regulation of muscle contraction, contributing to the muscle weakness. To address this question, we studied a broad range of contractile characteristics in skinned muscle fibres from the two patients and eight healthy controls. Results showed decreases (i) in speed of contraction at saturated Ca²⁺ concentration (apparent rate constant of force redevelopment (k_tr) and unloaded shortening speed (V₀)); and (ii) in contraction sensitivity to Ca²⁺ concentration, in fibres from patients compared with controls, suggesting that the mutation has a negative effect on contractile function, contributing to the muscle weakness. To investigate whether these negative impacts are reversible, we exposed skinned muscle fibres to the Ca²⁺ sensitizer EMD 57033. In fibres from patients, 30 µM of EMD 57033 (i) had no effect on speed of contraction (k_tr and V₀) at saturated Ca²⁺ concentration but (ii) increased Ca²⁺ sensitivity of contraction, suggesting a potential therapeutic approach in patients carrying the E41K β-Tm mutation.

(Received 7 March 2008; accepted after revision 16 April 2008; first published online 17 April 2008)
Corresponding author J. Ochala: Department of Neuroscience, Clinical Neurophysiology, University Hospital, Entrance 85, 3rd floor, SE-751 85 Uppsala, Sweden. Email: julien.ochala{at}neurofys.uu.se

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				S. Marston How does genotype define phenotype? Microphysiology of a tropomyosin mutation in situ shows the limitations of reductionism J. Physiol., June 15, 2008; 586(12): 2821 - 2821. [Full Text] [PDF]