Altered Ca2+ signaling in skeletal muscle fibers of the R6/2 mouse, a model of Huntington’s disease

Abstract

Huntington's disease (HD) is caused by an expanded CAG trinucleotide repeat within the gene encoding the protein huntingtin. The resulting elongated glutamine (poly-Q) sequence of mutant huntingtin (mhtt) affects both central neurons and skeletal muscle. Recent reports suggest that ryanodine receptor-based Ca(2+) signaling, which is crucial for skeletal muscle excitation-contraction coupling (ECC), is changed by mhtt in HD neurons. Consequently, we searched for alterations of ECC in muscle fibers of the R6/2 mouse, a mouse model of HD. We performed fluorometric recordings of action potentials (APs) and cellular Ca(2+) transients on intact isolated toe muscle fibers (musculi interossei), and measured L-type Ca(2+) inward currents on internally dialyzed fibers under voltage-clamp conditions. Both APs and AP-triggered Ca(2+) transients showed slower kinetics in R6/2 fibers than in fibers from wild-type mice. Ca(2+) removal from the myoplasm and Ca(2+) release flux from the sarcoplasmic reticulum were characterized using a Ca(2+) binding and transport model, which indicated a significant reduction in slow Ca(2+) removal activity and Ca(2+) release flux both after APs and under voltage-clamp conditions. In addition, the voltage-clamp experiments showed a highly significant decrease in L-type Ca(2+) channel conductance. These results indicate profound changes of Ca(2+) turnover in skeletal muscle of R6/2 mice and suggest that these changes may be associated with muscle pathology in HD.

DOI: 10.1085/jgp.201411255

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Cite this paper

@inproceedings{Braubach2014AlteredCS, title={Altered Ca2+ signaling in skeletal muscle fibers of the R6/2 mouse, a model of Huntington’s disease}, author={Peter Braubach and Murat Orynbayev and Zoita Andronache and Tanja Hering and Georg Bernhard Landwehrmeyer and Katrin S Lindenberg and Werner Melzer}, booktitle={The Journal of general physiology}, year={2014} }