Channelopathies of Skeletal Muscle Excitability

Abstract

Familial disorders of skeletal muscle excitability were initially described early in the last century and are now known to be caused by mutations of voltage-gated ion channels. The clinical manifestations are often striking, with an inability to relax after voluntary contraction (myotonia) or transient attacks of severe weakness (periodic paralysis). An essential feature of these disorders is fluctuation of symptoms that are strongly impacted by environmental triggers such as exercise, temperature, or serum K+ levels. These phenomena have intrigued physiologists for decades, and in the past 25 years the molecular lesions underlying these disorders have been identified and mechanistic studies are providing insights for therapeutic strategies of disease modification. These familial disorders of muscle fiber excitability are “channelopathies” caused by mutations of a chloride channel (ClC-1), sodium channel (NaV1.4), calcium channel (CaV1.1) and several potassium channels (Kir2.1, Kir2.6, Kir3.4). This review provides a synthesis of the mechanistic connections between functional defects of mutant ion channels, their impact on muscle excitability, how these changes cause clinical phenotypes, and approaches toward therapeutics.

Inhibiting persistent inward sodium currents prevents myotonia

“…Hitherto, it was thought that treatments eliminate myotonia via effects on transient Na + channels that lead to elevation of AP threshold 1, 31. Moreover, the previous model did not address termination of myotonia.…”

“…In both the autosomal dominant (Thomsen) and recessive (Becker) forms of myotonia congenita, loss of function mutations in the ClC‐1 gene ( CLCN1 ) cause muscle hyperexcitability 1, 2, 3. However, it has remained unclear what excitatory events trigger myotonic APs in the absence of the stabilizing ClC‐1 current.…”

“…Myotonia congenita is a member of a group of inherited skeletal muscle diseases known as the nondystrophic myotonias1, 2, 3 and results from a loss‐of‐function in the muscle chloride channel (ClC‐1) 4, 5, 6. The debilitating slowed muscle relaxation experienced by patients with myotonia congenita is caused by involuntary firing of action potentials (APs; myotonia).…”

“…Although it is well established that a decrease in ClC‐1 current causes muscle hyperexcitability, the excitatory events that trigger myotonic APs are not fully understood. Because of this, the mainstay of therapy remains avoiding activities that trigger myotonia,1 which can include running, walking, or other daily activities. Alternatively, drugs that block Na + channels, such as mexiletine, are used to reduce excitability 1, 2, 3.…”

“…Because of this, the mainstay of therapy remains avoiding activities that trigger myotonia,1 which can include running, walking, or other daily activities. Alternatively, drugs that block Na + channels, such as mexiletine, are used to reduce excitability 1, 2, 3. However, many patients suffer side effects or incomplete symptom resolution.…”