title: Altered Ca(2+) 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.
authors.affiliation: Institute of Applied Physiology and Department of Neurology, Ulm University, D-89081 Ulm, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Braubach
authors.affiliation: Institute of Applied Physiology and Department of Neurology, Ulm University, D-89081 Ulm, Germany.
authors.forename: Murat
authors.initials: M
authors.lastname: Orynbayev
authors.affiliation: Institute of Applied Physiology and Department of Neurology, Ulm University, D-89081 Ulm, Germany.
authors.forename: Zoita
authors.initials: Z
authors.lastname: Andronache
authors.affiliation: Institute of Applied Physiology and Department of Neurology, Ulm University, D-89081 Ulm, Germany Institute of Applied Physiology and Department of Neurology, Ulm University, D-89081 Ulm, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Hering
authors.affiliation: Institute of Applied Physiology and Department of Neurology, Ulm University, D-89081 Ulm, Germany.
authors.forename: Georg Bernhard
authors.initials: GB
authors.lastname: Landwehrmeyer
authors.affiliation: Institute of Applied Physiology and Department of Neurology, Ulm University, D-89081 Ulm, Germany.
authors.forename: Katrin S
authors.initials: KS
authors.lastname: Lindenberg
authors.affiliation: Institute of Applied Physiology and Department of Neurology, Ulm University, D-89081 Ulm, Germany werner.melzer@uni-ulm.de.
authors.forename: Werner
authors.initials: W
authors.lastname: Melzer
mesh_terms: D000200:Action Potentials; D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling; D056966:Excitation Contraction Coupling; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018485:Muscle Fibers, Skeletal / Q000378:metabolism* / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics
chemical_list: D020746:Calcium Channels, L-Type; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse