Isotonic contractile impairment due to genetic CLC-1 chloride channel deficiency in myotonic mouse diaphragm muscle.
The hallmark of genetic CLC-1 chloride channel deficiency in myotonic humans, goats and mice is delayed muscle relaxation resulting from persistent electrical discharges. In addition to the ion channel defect, muscles from myotonic humans and mice also have major changes in fibre type and myosin isoform composition, but the extent to which this affects isometric contractions remains controversial. Many muscles, including the diaphragm, shorten considerably during normal activities, but shortening contractions have never been assessed in myotonic muscle. The present study tested the hypothesis that CLC-1 deficiency leads to an impairment of muscle isotonic contractile performance. This was tested in vitro on diaphragm muscle from SWR/J-Clcn1(adr-mto)/J myotonic mice. The CLC-1-deficient muscle demonstrated delayed relaxation, as expected. During the contractile phase, there were significant reductions in power and work across a number of stimulation frequencies and loads in CLC-1-deficient compared with normal muscle, the magnitude of which in many instances exceeded 50%. Reductions in shortening and velocity of shortening occurred, and were more pronounced when calculated as a function of absolute than relative load. However, the maximal unloaded shortening velocity calculated from Hill's equation was not altered significantly. The impaired isotonic contractile performance of CLC-1-deficient muscle persisted during fatigue-inducing stimulation. These data indicate that genetic CLC-1 chloride channel deficiency in mice not only produces myotonia but also substantially worsens the isotonic contractile performance of diaphragm muscle.
van Lunteren
Erik
E
Pulmonary and Critical Care Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA. exv4@cwru.edu
Pollarine
Jennifer
J
Moyer
Michelle
M
D000818:Animals; D018118:Chloride Channels / Q000172:deficiency* / Q000502:physiology; D003964:Diaphragm / Q000502:physiology; D007551:Isotonic Contraction / Q000502:physiology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D018763:Muscle Fatigue / Q000502:physiology; D009126:Muscle Relaxation / Q000502:physiology; D009224:Myotonia Congenita / Q000503:physiopathology*
C086321:CLC-1 channel; D018118:Chloride Channels