A Small-Molecule Approach to Restore a Slow-Oxidative Phenotype and Defective CaMKIIβ Signaling in Limb Girdle Muscular Dystrophy

Cell Reports Medicine

Irina Kramerova¹  Elizabeth M. McNally²  Huan Meng³  April D. Pyle⁴  Ekaterina Mokhonova⁵  Varghese John⁵  Melissa J. Spencer⁵  Diana Becerra⁵  Jian Liu⁵  Jesus Campagna⁵  Robert Damoiseaux⁶ 

[1] Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA;Center for Genetic Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA;Department of Medicine, David Geffen School of Medicine and California Nanosystems Institute, University of California, Los Angeles, Los Angeles, CA, USA;Department of Microbiology, Immunology and Medical Genetics, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, USA;Department of Neurology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, USA;Department of Pharmacology, David Geffen School of Medicine and Molecular Screening Shared Resource, Crump Imaging Institute, University of California, Los Angeles, Los Angeles, CA, USA;

关键词: calpain;    high-throughput screen;    muscle;    calcium calmodulin kinase;    CaMK signaling;    exercise;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary: 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.

【 授权许可】

Unknown