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

doi:10.1016/j.xcrm.2020.100122

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^*

^*Corresponding author for this work

Medicine, Cardiology Division

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

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.

Original language	English (US)
Article number	100122
Journal	Cell Reports Medicine
Volume	1
Issue number	7
DOIs	https://doi.org/10.1016/j.xcrm.2020.100122
State	Published - Oct 20 2020

Funding

This work was largely supported through a generous donation from the MyDirectives Universal Advance Digital Directive . In addition, the work was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases through a Wellstone Cooperative Muscular Dystrophy Center ( U54AR052646 ) and a P30 Muscular Dystrophy Core Center ( NIAMS-P30AR057230 ), as well as through the NIH National Center for Advancing Translational Science (NCATS) UCLA CTSI grant no. UL1TR001881 (seed grant) and support from Strongbridge Biopharma . The authors would like to thank Ms. Jane Wen for technical support and Dr. Ellen Welch, Mr. Jeff Zucker, and Mr. Bhulo Kansagra for helpful discussions.

Keywords

CaMK signaling
calcium calmodulin kinase
calpain
calpainopathy
exercise
fiber type
high-throughput screen
limb girdle muscular dystrophy
mitochondria
muscle

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.xcrm.2020.100122

Cite this

Liu, J., Campagna, J., John, V., Damoiseaux, R., Mokhonova, E., Becerra, D., Meng, H., McNally, E. M., Pyle, A. D., Kramerova, I., & Spencer, M. J. (2020). A Small-Molecule Approach to Restore a Slow-Oxidative Phenotype and Defective CaMKIIβ Signaling in Limb Girdle Muscular Dystrophy. Cell Reports Medicine, 1(7), Article 100122. https://doi.org/10.1016/j.xcrm.2020.100122

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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.",

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AU - Damoiseaux, Robert

AU - Mokhonova, Ekaterina

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AB - 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.

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

Abstract

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Keywords

ASJC Scopus subject areas

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