DR. MELISSA SPENCER, DAVID GEFFEN SCHOOL OF MEDICINE AT UCLA

The limb girdle muscular dystrophies (LGMDs) are genetically inherited diseases defined by progressive, proximal muscle wasting. Fifteen distinct autosomal recessive LGMD genes have been identified, the majority of which are associated with the dystrophin glycoprotein complex and involve membrane fragility as a primary pathogenic feature. The most prevalent form of LGMD, called LGMD2A, results from mutations in the gene encoding the muscle specific calcium-dependent protease calpain 3 (capn3, C3). Unlike most other LGMDs, “calpainopathy” does not involve membrane damage as a primary feature; therefore, the mechanisms of this disease are quite different from other LGMDs, and have remained mysterious since the gene defect was discovered by Jacques Beckmann’s lab in 1997.

Over the last decade the Spencer lab has generated numerous genetically modified mice, which have been used to elucidate C3’s biological role and to understand pathomechanisms of calpainopathy. Most importantly, they generated calpain 3 knock out mice (C3KO) that revealed a role for C3 in muscle growth and adaptation. Furthermore, a structural role for C3 at the muscle triad was identified, involving stabilization of the Ryanodine Receptor (RyR). Loss of C3 leads to reduced calcium release upon muscle excitation-contraction coupling. Subsequently, it was demonstrated that at least one Ca2+ mediated signaling pathway, involving calcium-calmodulin kinase (CaMK), is dysfunctional in the absence of C3. Based on the known features of CaMK signaling, loss of this pathway helps explain the impaired muscle adaptation response in C3 deficient muscles. In the current investigation, a second Ca2+ mediated signaling pathway will be explored for its potential role in calpainopathy. This pathway, called the titin kinase signaling (TK) pathway, has a known function in transcriptional responses to muscle loading in cardiac cells, and our preliminary data suggest it may also be defective in calpainopathy. Calpain 3 binds to titin, very close to the titin kinase domain and therefore, it may regulate its activity directly. Like CaMK signaling, this pathway presents a promising candidate for therapeutic intervention. In this investigation, the biochemical mechanisms by which C3 interacts with and influences TK signaling will be assessed. In addition, genetically modified mice will be created to determine whether overriding the TK signaling defect improves the calpainopathy phenotype. These studies are the first to identify defective signaling as the basis of the growth and adaptation defect in calpainopathy and represent promising therapeutic targets.

C3 organized and hosted the first U.S. scientific conference focused solely on LGMD2A: "Clinical Characteristics and Pathogenic Mechanisms of LGMD2A/calpainopathy". On October 27, 2011, twenty-four esteemed scientists from eight countries attended the workshop. A book containing abstracts submitted by the presenters is available here. The second global conference organized by C3 is slated for November 2013.

C3 sponsored "2012 New Directions in Biology and Disease of Skeletal Muscle Conference", which highlighted current developments in muscle biology, disease, and therapy with presentations by leading international researchers. More information is available here.

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C3KO mouse expression analysis: downregulation of the muscular dystrophy Ky protein and alterations in muscle aging, click here

Calpain 3, the Gatekeeper of Proper Assembly, Turnover and Maintenance, click here

Molecular and Cellular Basis of Calpainopathy, click here

Slug is a Novel Downstream Target of MyoD, click here

For a review of calpainopathy sponsored by GeneReviews
click here

For a review of calpainopathy sponsored the National Center for Biotechnology Information,
click here