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

Abstract

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.

Alterations in the structural characteristics of rectus abdominis muscles caused by diabetes and pregnancy: A comparative study of the rat model and women

“…GLUT4 expression compared to fast fiber [52,53]. Similar changes are seen in cancer cachexia [54], aging-related sarcopenia [55], and Huntington's Disease [56]. The differences in the slow fiber area between the MHP (rat) and GDM (human) groups may be due to the relatively short pregnancy time and the higher number of fetuses in the rats and high weight gain in the humans.…”

Depressed Synaptic Transmission and Reduced Vesicle Release Sites in Huntington's Disease Neuromuscular Junctions

“…In support of primary muscle defects, motor symptoms were shown to precede the onset of neurological symptoms in a marathon runner with HD (Kosinski et al, 2007). Moreover, a number of studies have demonstrated pathological changes in HD muscle, including metabolic and mitochondrial defects (Lodi et al, 2000;Turner et al, 2007;Mielcarek et al, 2015), atrophy (Ribchester et al, 2004;She et al, 2011;Ehrnhoefer et al, 2014), reduced muscle strength (Busse et al, 2008;Hering et al, 2016), and a reduced expression of genes necessary for normal muscle differentiation (Luthi-Carter et al, 2002;Strand et al, 2005). Additionally, we previously discovered that skeletal muscle from R6/2 transgenic HD mice is hyperexcitable due to decreased currents through chloride (ClC-1) and inwardly rectifying potassium (Kir) channels, which correlated with aberrant mRNA processing and lower levels of mature full-length mRNAs for ClC-1 and Kir channels (Waters et al, 2013).…”

Frequency-Dependent Reaction of the Triceps Surae Muscle of the Mouse During Electromyostimulation

“…The depletion of the Na + (or the accumulation of K + ) could reduce the muscle membrane excitability sufficiently to explain the force loss during a higher frequency (Moritani et al, 1985). Frontiers in Physiology | www.frontiersin.org Due to different stimulation protocols and other environmental conditions, the comparison of the results presented here to other animal studies remains complicated (Guo et al, 2012;Kobayashi et al, 2012;Tsutaki et al, 2013;Hering et al, 2016;Li et al, 2016;Valenzuela et al, 2017). Nevertheless, similar results could be observed in the behavior of the muscle during stimulation with different frequencies, even if the environmental influences and the way of stimulation of the muscle (ex vivo, needle electrode) were different.…”

“…The question now arises why we could not find an increased shortening at higher frequencies, what the force frequency relationship (FFR) suggests. Studies found an increase in muscle tension (Guo et al, 2012) or strength production (Hering et al, 2016) due to an increase in the frequency in animal experiments. First of all, it has to be taken into account that our experiments are carried out ex vivo, using a needle electrode, which complicates the comparability to in vivo or in vitro studies.…”

“…20 Hz seem to have a positive influence on strength increases in the m. soleus of the mouse during a 14-day stimulation period (two times daily per 3 h of stimulation), furthermore positive influences on the development of the satellite cells can be determined (Guo et al, 2012). Exemplary studies showed an increased force production and tension with increasing frequency (Guo et al, 2012;Hering et al, 2016). However, an increased frequency cannot be maintained indefinitely.…”