Novel Mechanisms Underlying Warm-up and Percussion Myotonia in Myotonia Congenita
Dan Halm (Committee Member), J. Ashot Kozak (Committee Member), Mark Rich (Advisor), Courtney Sulentic (Committee Member), Andrew Voss (Committee Member)
Doctor of Philosophy (PhD)
Patients with myotonia congenita have muscle hyperexcitability due to loss-of-function mutations in the ClC-1 chloride channel in skeletal muscle, which causes spontaneous firing of muscle action potentials (myotonia), producing muscle stiffness. Triggers for myotonia can occur voluntarily at the neuromuscular junction or involuntarily by striking the muscle with a reflex hammer (percussion myotonia). In patients, muscle stiffness lessens with exercise, a change known as the warm-up phenomenon. Our goal was to identify the mechanism underlying warm-up and percussion myotonia and to use this information to guide development of novel therapies. To determine these underlying mechanisms, we used a drug to eliminate muscle contraction. This allowed for prolonged intracellular recording from individual muscle fibers during induction of warm-up and stretch-induced percussion myotonia in a mouse model of myotonia congenita. To investigate the warm-up phenomenon exercise was modelled in vitro by delivering 5000 action potentials at 20 Hz. Stretch-induced percussion myotonia was modelled in vitro by fabricating a blunt glass probe to stretch the muscle fiber mimicking the strike of the reflex hammer. Changes to action potential morphology following active exercise suggests slow inactivation of sodium channels as the mechanism contributing to warm-up. Reductions to stretch-induced depolarizations and myotonia in response to mechanosensitive channel blockers strongly suggests the involvement of a stretch activated channel as the trigger for percussion myotonia. We propose that stretch seen during percussion myotonia is similar to stretch experienced by an antagonistic muscle while yielding to contraction. This stretch-induced myotonia may be contributing to patient stiffness. Drugs were investigated as potential therapeutics for accelerating warm-up or block of stretch activation. We found that enhancement of sodium channel slow inactivation using ranolazine reduces stimulation induced myotonic stiffness.
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