TY - JOUR

T1 - Effects of a R133W β-tropomyosin mutation on regulation of muscle contraction in single human muscle fibres

AU - Ochala, Julien

AU - Li, Mingxin

AU - Tajsharghi, Homa

AU - Kimber, Eva

AU - Tulinius, Mar

AU - Oldfors, Anders

AU - Larsson, Lars

PY - 2007/6/1

Y1 - 2007/6/1

N2 - A novel R133W β-tropomyosin (β-Tm) mutation, associated with muscle weakness and distal limb deformities, has recently been identified in a woman and her daughter. The muscle weakness was not accompanied by progressive muscle wasting or histopathological abnormalities in tibialis anterior muscle biopsy specimens. The aim of the present study was to explore the mechanisms underlying the impaired muscle function in patients with the β-Tm mutation. Maximum force normalized to fibre cross-sectional area (specific force, SF), maximum velocity of unloaded shortening (V0), apparent rate constant of force redevelopment (ktr) and force-pCa relationship were evaluated in single chemically skinned muscle fibres from the two patients carrying the β-Tm mutation and from healthy control subjects. Significant differences in regulation of muscle contraction were observed in the type I fibres: a lower SF (P < 0.05) and ktr (P < 0.01), and a faster V0 (P < 0.05). The force-pCa relationship did not differ between patient and control fibres, indicating an unaltered Ca2+ activation of contractile proteins. Collectively, these results indicate a slower cross-bridge attachment rate and a faster detachment rate caused by the R133W β-Tm mutation. It is suggested that the R133W β-Tm mutation induces alteration in myosin-actin kinetics causing a reduced number of myosin molecules in the strong actin-binding state, resulting in overall muscle weakness in the absence of muscle wasting.

AB - A novel R133W β-tropomyosin (β-Tm) mutation, associated with muscle weakness and distal limb deformities, has recently been identified in a woman and her daughter. The muscle weakness was not accompanied by progressive muscle wasting or histopathological abnormalities in tibialis anterior muscle biopsy specimens. The aim of the present study was to explore the mechanisms underlying the impaired muscle function in patients with the β-Tm mutation. Maximum force normalized to fibre cross-sectional area (specific force, SF), maximum velocity of unloaded shortening (V0), apparent rate constant of force redevelopment (ktr) and force-pCa relationship were evaluated in single chemically skinned muscle fibres from the two patients carrying the β-Tm mutation and from healthy control subjects. Significant differences in regulation of muscle contraction were observed in the type I fibres: a lower SF (P < 0.05) and ktr (P < 0.01), and a faster V0 (P < 0.05). The force-pCa relationship did not differ between patient and control fibres, indicating an unaltered Ca2+ activation of contractile proteins. Collectively, these results indicate a slower cross-bridge attachment rate and a faster detachment rate caused by the R133W β-Tm mutation. It is suggested that the R133W β-Tm mutation induces alteration in myosin-actin kinetics causing a reduced number of myosin molecules in the strong actin-binding state, resulting in overall muscle weakness in the absence of muscle wasting.

UR - http://www.scopus.com/inward/record.url?scp=34250009728&partnerID=8YFLogxK

U2 - 10.1113/jphysiol.2007.129759

DO - 10.1113/jphysiol.2007.129759

M3 - Journal article

C2 - 17430991

AN - SCOPUS:34250009728

VL - 581

SP - 1283

EP - 1292

JO - The Journal of Physiology

JF - The Journal of Physiology

SN - 0022-3751

IS - 3

ER -