| First Author | Liu J | Year | 2020 |
| Journal | Cell Rep Med | Volume | 1 |
| Issue | 7 | Pages | 100122 |
| PubMed ID | 33205074 | Mgi Jnum | J:328077 |
| Mgi Id | MGI:6728363 | Doi | 10.1016/j.xcrm.2020.100122 |
| Citation | Liu J, et al. (2020) A Small-Molecule Approach to Restore a Slow-Oxidative Phenotype and Defective CaMKIIbeta Signaling in Limb Girdle Muscular Dystrophy. Cell Rep Med 1(7):100122 |
| abstractText | 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 CaMKIIbeta 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 CaMKIIbeta 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. |
