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

Jian Liu; Jesus Campagna; Varghese John; Robert Damoiseaux; Ekaterina Mokhonova; Diana Becerra; Huan Meng; Elizabeth M. McNally; April D. Pyle; Irina Kramerova; Melissa J. Spencer

Cell Reports Medicine (Oct 2020)

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

Jian Liu,
Jesus Campagna,
Varghese John,
Robert Damoiseaux,
Ekaterina Mokhonova,
Diana Becerra,
Huan Meng,
Elizabeth M. McNally,
April D. Pyle,
Irina Kramerova,
Melissa J. Spencer

Affiliations

Jian Liu: Department of Neurology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, USA
Jesus Campagna: Department of Neurology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, USA
Varghese John: Department of Neurology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, USA
Robert Damoiseaux: 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
Ekaterina Mokhonova: Department of Neurology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, USA
Diana Becerra: Department of Neurology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, USA
Huan Meng: Department of Medicine, David Geffen School of Medicine and California Nanosystems Institute, University of California, Los Angeles, Los Angeles, CA, USA
Elizabeth M. McNally: Center for Genetic Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
April D. Pyle: Department of Microbiology, Immunology and Medical Genetics, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA
Irina Kramerova: Department of Neurology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, USA; Corresponding author
Melissa J. Spencer: Department of Neurology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, USA; Corresponding author

Journal volume & issue: Vol. 1, no. 7
p. 100122

Abstract

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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.

Published in Cell Reports Medicine

ISSN: 2666-3791 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Medicine (General)
Website: https://www.cell.com/cell-reports-medicine

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