FER-1/Dysferlin promotes cholinergic signaling at the neuromuscular junction in C. elegans and mice.
Dysferlin is a member of the evolutionarily conserved ferlin gene family. Mutations in Dysferlin lead to Limb Girdle Muscular Dystrophy 2B (LGMD2B), an inherited, progressive and incurable muscle disorder. However, the molecular mechanisms underlying disease pathogenesis are not fully understood. We found that both loss-of-function mutations and muscle-specific overexpression of C. elegans fer-1, the founding member of the Dysferlin gene family, caused defects in muscle cholinergic signaling. To determine if Dysferlin-dependent regulation of cholinergic signaling is evolutionarily conserved, we examined the in vivo physiological properties of skeletal muscle synaptic signaling in a mouse model of Dysferlin-deficiency. In addition to a loss in muscle strength, Dysferlin -/- mice also exhibited a cholinergic deficit manifested by a progressive, frequency-dependent decrement in their compound muscle action potentials following repetitive nerve stimulation, which was observed in another Dysferlin mouse model but not in a Dysferlin-independent mouse model of muscular dystrophy. Oral administration of Pyridostigmine bromide, a clinically used acetylcholinesterase inhibitor (AchE.I) known to increase synaptic efficacy, reversed the action potential defect and restored in vivo muscle strength to Dysferlin -/- mice without altering muscle pathophysiology. Our data demonstrate a previously unappreciated role for Dysferlin in the regulation of cholinergic signaling and suggest that such regulation may play a significant pathophysiological role in LGMD2B disease.
Department of Physiology, Richards Research Building A702, University of Pennsylvania , Philadelphia, PA 19104 , USA ; Pennsylvania Muscle Institute, 700A Clinical Research Building, University of Pennsylvania , Philadelphia, PA 19104 , USA.
Predrag
P
Krajacic
Emidio E
EE
Pistilli
Jessica E
JE
Tanis
Tejvir S
TS
Khurana
S Todd
ST
Lamitina
Dysferlin; LGMD2B; Limb-girdle; Muscular dystrophy; Synaptic transmission