A Small-Molecule Approach to Restore a Slow-Oxidative Phenotype and Defective CaMKIIβ Signaling in Limb Girdle Muscular Dystrophy
Year: 2020
Type: article
Abstract: Mutations in CAPN3 cause limb girdle muscular dystrophy R1 (LGMDR1, formerly LGMD2A) and lead to progressive and debilitating muscle wasting. Calpain 3 deficiency is associated with impaired CaMKIIβ signaling and blunted transcriptional programs that encode the slow-oxidative muscle phenotype. We conducted a high-throughput screen on a target of CaMKII ( Myl2 ) to identify compounds to override this signaling defect; 4 were tested in vivo in the Capn3 knockout (C3KO) model of LGMDR1. The leading compound, AMBMP, showed good exposure and was able to reverse the LGMDR1 phenotype in vivo , including improved oxidative properties, increased slow fiber size, and enhanced exercise performance. AMBMP also activated CaMKIIβ signaling, but it did not alter other pathways known to be associated with muscle growth. Thus, AMBMP treatment activates CaMKII and metabolically reprograms skeletal muscle toward a slow muscle phenotype. These proof-of-concept studies lend support for an approach to the development of therapeutics for LGMDR1.
Source: Cell Reports Medicine
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,200
Funders: National Institutes of Health, National Institute of Neurological Disorders and Stroke, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Advancing Translational Sciences, Clinical and Translational Science Institute, University of California, Los Angeles
Awards: FAILED REGENERATION IN THE MUSCULAR DYSTROPHIES: INFLAMMATION, FIBROSIS AND FAT, UCLA Muscular Dystrophy Core Center, G562934659, Mechanisms Underlying Limb Girdle Muscular Dystrophy2A Due to Calpain 3 Mutations, Optimizing and validation of gene therapy vectors to treat limb girdle muscular dystophy, Reprogramming and Directed Differentiation of Skeletal Muscle Cells from hPSCs, UCLA Clinical and Translational Science Institute
OpenAlex ID: W3093487358