Defective regulation of contractile function in muscle fibres carrying an E41K β-tropomyosin mutation
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Defective regulation of contractile function in muscle fibres carrying an E41K β-tropomyosin mutation. / Ochala, Julien; Li, Meishan; Ohlsson, Monica; Oldfors, Anders; Larsson, Lars.
In: Journal of Physiology, Vol. 586, No. 12, 15.06.2008, p. 2993-3004.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Defective regulation of contractile function in muscle fibres carrying an E41K β-tropomyosin mutation
AU - Ochala, Julien
AU - Li, Meishan
AU - Ohlsson, Monica
AU - Oldfors, Anders
AU - Larsson, Lars
PY - 2008/6/15
Y1 - 2008/6/15
N2 - 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 (ktr) 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 μ m of EMD 57033 (i) had no effect on speed of contraction (ktr 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.
AB - 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 (ktr) 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 μ m of EMD 57033 (i) had no effect on speed of contraction (ktr 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.
UR - http://www.scopus.com/inward/record.url?scp=45249099152&partnerID=8YFLogxK
U2 - 10.1113/jphysiol.2008.153650
DO - 10.1113/jphysiol.2008.153650
M3 - Journal article
C2 - 18420702
AN - SCOPUS:45249099152
VL - 586
SP - 2993
EP - 3004
JO - The Journal of Physiology
JF - The Journal of Physiology
SN - 0022-3751
IS - 12
ER -
ID: 245665323