Abstract
SummaryDysferlin 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.
Highlights
Limb-Girdle Muscular Dystrophy 2B, or Dysferlinopathy, is an incurable muscle disorder in which patients usually present in the second or third decade of life with proximal and/or distal muscle weakness, elevated serum creatine kinase (CK) levels, and generally slow disease progression (Amato and Brown, 2011)
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
Summary
Limb-Girdle Muscular Dystrophy 2B, or Dysferlinopathy, is an incurable muscle disorder in which patients usually present in the second or third decade of life with proximal and/or distal muscle weakness, elevated serum creatine kinase (CK) levels, and generally slow disease progression (Amato and Brown, 2011). Recent studies demonstrate that restoration of Dyferlin gene expression solely in the skeletal muscle is sufficient to rescue all disease phenotypes (Millay et al, 2009), suggesting that the immune functions of Dysferlin play minor roles in disease pathogenesis and that the pathophysiological defect(s) associated with the loss of Dysferlin is based within the muscle. Defining these muscle-specific roles of Dysferlin could provide insight into LGMD2B pathogenesis and may suggest therapeutic opportunities for this untreatable disease
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