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

Cell Reports Medicine
Jian LiuMelissa J Spencer

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.

References

Jan 1, 1994·Annual Review of Physiology·C Franzini-Armstrong, A O Jorgensen
Oct 1, 1995·Mammalian Genome : Official Journal of the International Mammalian Genome Society·I RichardJ S Beckmann
Oct 21, 2003·The Journal of Physiology·Adam J Rose, Mark Hargreaves
May 13, 2004·Human Molecular Genetics·I KramerovaMelissa J Spencer
Jun 18, 2005·Human Molecular Genetics·Irina KramerovaMelissa J Spencer
Jul 16, 2005·Journal of Applied Physiology·Eva R Chin
Aug 16, 2005·Cell Calcium·Aimee D Kohn, Randall T Moon
Sep 20, 2006·Molecular and Cellular Biology·Irina KramerovaMelissa J Spencer
Oct 26, 2007·Development·Matthew J Potthoff, Eric N Olson
Jan 1, 2009·International Journal of Cell Biology·Govindan DayanithiStephen Baghdiguian
Apr 20, 2010·Pflügers Archiv : European journal of physiology·Jesper OlesenHenriette Pilegaard
Feb 8, 2011·Journal of Molecular Biology·Koichi OjimaHiroyuki Sorimachi
Dec 20, 2011·Nature Cell Biology·Julia von MaltzahnMichael A Rudnicki
Sep 5, 2012·Trends in Cell Biology·Julia von MaltzahnMichael A Rudnicki
Nov 28, 2012·Proceedings of the National Academy of Sciences of the United States of America·Julia von MaltzahnMichael A Rudnicki
Feb 19, 2013·Neuropathology and Applied Neurobiology·M FaninC Angelini
Jul 4, 2013·Neurologia i neurochirurgia polska·Aleksandra A Nadaj-PaklezaA M Kamińska
Jan 23, 2016·The Journal of Experimental Biology·Hans Hoppeler
Apr 16, 2016·Annals of Clinical and Translational Neurology·Isabelle RichardJon Andoni Urtizberea
Jun 5, 2016·Brain : a Journal of Neurology·John VissingMorten Duno
Jan 11, 2017·Reproduction : the Official Journal of the Society for the Study of Fertility·Paula TribuloPeter J Hansen
Nov 9, 2017·Diabetes & Vascular Disease Research : Official Journal of the International Society of Diabetes and Vascular Disease·Ian Ackers, Ramiro Malgor
Dec 1, 2018·Journal of Neuropathology and Experimental Neurology·Riyad El-KhouryMamdouha Ahdab-Barmada
Dec 12, 2018·Journal of Cellular Physiology·Eskandar TaghizadehAmirhossein Sahebkar
May 21, 2019·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Wei LiuMonkol Lek
May 21, 2020·The EMBO Journal·Rebeca Acin-PerezOrian S Shirihai

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Methods Mentioned

BETA
biopsies
PCR
Assay
protein Assay

Key Resources (RRID) Mentioned

CVCL_UR38
IMSR_JAX

Software Mentioned

Prism ( GraphPad )
Axio Vision

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