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

Braubach, Peter; Orynbayev, Murat; Andronache, Zoita; Hering, Tanja; Landwehrmeyer, G. Bernhard; Lindenberg, Katrin S.; Melzer, Werner

doi:10.1085/jgp.201411255

Cited by 26 publications

(36 citation statements)

References 126 publications

(277 reference statements)

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“…Decreased RNA expression for various proteins involved in the Ca 2+ signaling cascade of muscle activation (ryanodine receptor, calsequestrin, parvalbumin, troponin) have been reported [31]. Recently, our group found a decrease in the rates of both Ca 2+ release from the SR and removal of released Ca 2+ in isolated interosseous muscle fibers of R6/2 mice [36]. Lower Ca 2+ release would decrease force production, and slower Ca 2+ removal, caused by changes in Ca 2+ buffering or transport, should decrease the relaxation speed of twitch force and may consequently contribute to the observed left-shift in the force-frequency curve.…”

Section: Discussionmentioning

confidence: 99%

“…The gels (8% polyacrylamide) were loaded with 5 μg extracted protein from whole muscle or total single fiber lysate [38] and stained with Roti®-Blue (Carl Roth; Karlsruhe, Germany) and the protein bands in the scanned gels were integrated using the software ImageJ (National Institutes of Health). Quantitative Western Blot analysis to identify the stained MyHC isoforms was performed as described by Braubach et al [36]. …”

Section: Methodsmentioning

confidence: 99%

“…Mielcarek et al [30] report significant transcriptional upregulation of Myh7, the gene encoding the slow isoform MyHCI, in several fast twitch muscles. In contrast, determining protein alterations in R6/2 interosseus muscle (containing predominantly fast type IIA fibers), our group found several alterations in the MyLC protein pattern but none in MyHC isoforms that would have pointed to a significant fast to slow fiber type transition [36]. Therefore, our aim in this study was to specifically investigate the fast glycolytic extensor digitorum longus muscle (EDL) in comparison to the slow oxidative soleus (SOL) muscle to determine contractile properties and to quantify changes in muscle fiber type by determining relative alterations of the various myosin isoforms using electrophoretic protein separation and immunostaining.…”

Section: Introductionmentioning

confidence: 97%

“…Widespread mHTT-positive inclusion formation in several neuronal and non-neuronal tissues which include muscle have been observed in R6/2 mice [19, 24, 25, 27, 29]. Several studies have addressed skeletal muscle function in these mice and identified higher sensitivity of mitochondria for Ca 2+ -induced permeability transition [33], alterations in synaptic transmission and in Na + , K + and Cl - channels [34, 35] and compromised depolarization-triggered Ca 2+ release and removal activity and contraction [30, 36]. …”

Section: Introductionmentioning

confidence: 99%

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Fast-to-Slow Transition of Skeletal Muscle Contractile Function and Corresponding Changes in Myosin Heavy and Light Chain Formation in the R6/2 Mouse Model of Huntington’s Disease

et al. 2016

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Huntington´s disease (HD) is a hereditary neurodegenerative disease resulting from an expanded polyglutamine sequence (poly-Q) in the protein huntingtin (HTT). Various studies report atrophy and metabolic pathology of skeletal muscle in HD and suggest as part of the process a fast-to-slow fiber type transition that may be caused by the pathological changes in central motor control or/and by mutant HTT in the muscle tissue itself. To investigate muscle pathology in HD, we used R6/2 mice, a common animal model for a rapidly progressing variant of the disease expressing exon 1 of the mutant human gene. We investigated alterations in the extensor digitorum longus (EDL), a typical fast-twitch muscle, and the soleus (SOL), a slow-twitch muscle. We focussed on mechanographic measurements of excised muscles using single and repetitive electrical stimulation and on the expression of the various myosin isoforms (heavy and light chains) using dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) of whole muscle and single fiber preparations. In EDL of R6/2, the functional tests showed a left shift of the force-frequency relation and decrease in specific force. Moreover, the estimated relative contribution of the fastest myosin isoform MyHC IIb decreased, whereas the contribution of the slower MyHC IIx isoform increased. An additional change occurred in the alkali MyLC forms showing a decrease in 3f and an increase in 1f level. In SOL, a shift from fast MyHC IIa to the slow isoform I was detectable in male R6/2 mice only, and there was no evidence of isoform interconversion in the MyLC pattern. These alterations point to a partial remodeling of the contractile apparatus of R6/2 mice towards a slower contractile phenotype, predominantly in fast glycolytic fibers.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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Fast-to-Slow Transition of Skeletal Muscle Contractile Function and Corresponding Changes in Myosin Heavy and Light Chain Formation in the R6/2 Mouse Model of Huntington’s Disease

et al. 2016

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“…Lastly, there is a large group of human diseases presenting with complex dystonia that are seemingly linked to dysfunction of calcium, phosphate, or calcium‐sensitive potassium channels; as examples: episodic ataxia with interictal dystonia ( CACNA1A mutations); primary familial brain calcifications ( SLC20A2 mutations); and paroxysmal dyskinesia ( KCNMA1 mutations) . Deranged calcium dynamics have been proposed for other motor disorders, such as Huntington's disease and Parkinson's disease (PD) …”

Section: Abnormal Calcium Homeostasis In Dystoniamentioning

confidence: 99%

Novel Dystonia Genes: Clues on Disease Mechanisms and the Complexities of High‐Throughput Sequencing

2016

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Dystonia is a genetically heterogenous disease and a prototype disorder where next-generation sequencing has facilitated the identification of new pathogenic genes. This includes the first two genes linked to recessively inherited isolated dystonia, that is, HPCA (hippocalcin) and COL6A3 (collagen VI alpha 3). These genes are proposed to underlie cases of the so-called DYT2-like dystonia, while also reiterating two distinct pathways in dystonia pathogenesis. First, deficiency in HPCA function is thought to alter calcium homeostasis, a mechanism that has previously been forwarded for CACNA1A and ANO3. The novel myoclonus-dystonia genes KCTD17 and CACNA1B also implicate abnormal calcium signaling in dystonia. Second, the phenotype in COL6A3-loss-of-function zebrafish models argues for a neurodevelopmental defect, which has previously been suggested as a possible biological mechanism for THAP1, TOR1A, and TAF1 based on expression data. The newly reported myoclonus-dystonia gene, RELN, plays also a role in the formation of brain structures. Defects in neurodevelopment likewise seem to be a recurrent scheme underpinning mainly complex dystonias, for example those attributable to biallelic mutations in GCH1, TH, SPR, or to heterozygous TUBB4A mutations. To date, it remains unclear whether dystonia is a common phenotypic outcome of diverse underlying disease mechanisms, or whether the different genetic causes converge in a single pathway. Importantly, the relevance of pathways highlighted by novel dystonia genes identified by high-throughput sequencing depends on the confirmation of mutation pathogenicity in subsequent genetic and functional studies. However, independent, careful validation of genetic findings lags behind publications of newly identified genes. We conclude with a discussion on the characteristics of true-positive reports.

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Targeting microglia L‐type voltage‐dependent calcium channels for the treatment of central nervous system disorders

Hopp

2020

J of Neuroscience Research

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Calcium (Ca2+) is a ubiquitous mediator of a multitude of cellular functions in the central nervous system (CNS). Intracellular Ca2+ is tightly regulated by cells, including entry via plasma membrane Ca2+ permeable channels. Of specific interest for this review are L‐type voltage‐dependent Ca2+ channels (L‐VDCCs), due to their pleiotropic role in several CNS disorders. Currently, there are numerous approved drugs that target L‐VDCCs, including dihydropyridines. These drugs are safe and effective for the treatment of humans with cardiovascular disease and may also confer neuroprotection. Here, we review the potential of L‐VDCCs as a target for the treatment of CNS disorders with a focus on microglia L‐VDCCs. Microglia, the resident immune cells of the brain, have attracted recent attention for their emerging inflammatory role in several CNS diseases. Intracellular Ca2+ regulates microglia transition from a resting quiescent state to an “activated” immune‐effector state and is thus a valuable target for manipulation of microglia phenotype. We will review the literature on L‐VDCC expression and function in the CNS and on microglia in vitro and in vivo and explore the therapeutic landscape of L‐VDCC‐targeting agents at present and future challenges in the context of Alzheimer's disease, Parkinson's disease, Huntington's disease, neuropsychiatric diseases, and other CNS disorders.

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

Abstract: A mouse model of Huntington’s disease shows impaired calcium handling in skeletal muscle, potentially contributing to the pathology of the disease.

Cited by 26 publications

References 126 publications

Fast-to-Slow Transition of Skeletal Muscle Contractile Function and Corresponding Changes in Myosin Heavy and Light Chain Formation in the R6/2 Mouse Model of Huntington’s Disease

Fast-to-Slow Transition of Skeletal Muscle Contractile Function and Corresponding Changes in Myosin Heavy and Light Chain Formation in the R6/2 Mouse Model of Huntington’s Disease

Novel Dystonia Genes: Clues on Disease Mechanisms and the Complexities of High‐Throughput Sequencing

Targeting microglia L‐type voltage‐dependent calcium channels for the treatment of central nervous system disorders

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