Properties of slow- and fast-twitch muscle fibres in a mouse model of amyotrophic lateral sclerosis

Atkin, Julie D.; Scott, Rebecca J.; West, Jan M.; Lopes, Elizabeth C; Quah, Alvin Kee Jin; Cheema, Surindar S.

doi:10.1016/j.nmd.2005.02.005

Cited by 73 publications

(76 citation statements)

References 40 publications

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“…Morphometric analysis showed that Nogo-A levels correlated with the mean area of fast-twitch type II fibers, and many of them are small and present an angulated morphology ( Figure 4B). These data were identical to an earlier observation that fast-twitch muscle fibers were preferentially affected by ALS-induced denervation [31].…”

Section: Limb Muscle Atrophy In Transgenic Sod1 Pigssupporting

confidence: 91%

Species-dependent neuropathology in transgenic SOD1 pigs

Yang

Wang

Sun³

et al. 2014

Cell Res

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Mutations in the human copper/zinc superoxide dismutase 1 (hSOD1) gene cause familial amyotrophic lateral sclerosis (ALS). It remains unknown whether large animal models of ALS mimic more pathological events seen in ALS patients via novel mechanisms. Here, we report the generation of transgenic pigs expressing mutant G93A hSOD1 and showing hind limb motor defects, which are germline transmissible, and motor neuron degeneration in dose-and age-dependent manners. Importantly, in the early disease stage, mutant hSOD1 did not form cytoplasmic inclusions, but showed nuclear accumulation and ubiquitinated nuclear aggregates, as seen in some ALS patient brains, but not in transgenic ALS mouse models. Our findings revealed that SOD1 binds PCBP1, a nuclear poly(rC) binding protein, in pig brain, but not in mouse brain, suggesting that the SOD1-PCBP1 interaction accounts for nuclear SOD1 accumulation and that species-specific targets are key to ALS pathology in large mammals and in humans.

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Section: Limb Muscle Atrophy In Transgenic Sod1 Pigssupporting

confidence: 91%

Species-dependent neuropathology in transgenic SOD1 pigs

Yang

Wang

Sun³

et al. 2014

Cell Res

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“…Expression of MHC-1 protein was not altered, but specific maximal force and mitochondrial enzymes were unchanged in the soleus muscles of mice lacking neurotrophin-4 and exhibiting neuromuscular junction dysfunctions (8). In a mouse model of amyotrophic lateral sclerosis (expression of a mutant SOD1 gene), a decrease in twitch kinetics was observed in the soleus of presymptomatic mice, but there is a shift toward a fast type of muscle phenotype, without modification in maximal force and muscle atrophy (4,16,17,25).…”

Section: Discussionmentioning

confidence: 93%

Slow myosin heavy chain expression in the absence of muscle activity

Agbulut

Vignaud²,

Hourdé³

et al. 2009

American Journal of Physiology-Cell Physiology

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Innervation has been generally accepted to be a major factor involved in both triggering and maintaining the expression of slow myosin heavy chain (MHC-1) in skeletal muscle. However, previous findings from our laboratory have suggested that, in the mouse, this is not always the case (30). Based on these results, we hypothesized that neurotomy would not markedly reduced the expression of MHC-1 protein in the mouse soleus muscles. In addition, other cellular, biochemical, and functional parameters were also studied in these denervated soleus muscles to complete our study. Our results show that denervation reduced neither the relative amount of MHC-1 protein, nor the percentage of muscle fibers expressing MHC-1 protein (P Ͼ 0.05). The fact that MHC-1 protein did not respond to muscle inactivity was confirmed in three different mouse strains (129/SV, C57BL/6, and CD1). In contrast, all of the other histological, biochemical, and functional muscle parameters were markedly altered by denervation. Cross-sectional area (CSA) of muscle fibers, maximal tetanic isometric force, maximal velocity of shortening, maximal power, and citrate synthase activity were all reduced in denervated muscles compared with innervated muscles (P Ͻ 0.05). Contraction and one-half relaxation times of the twitch were also increased by denervation (P Ͻ 0.05). Addition of tenotomy to denervation had no further effect on the relative expression of MHC-1 protein (P Ͼ 0.05), despite a greater reduction in CSA and citrate synthase activity (P Ͻ 0.05). In conclusion, a deficit in neural input leads to marked atrophy and reduction in performance in mouse soleus muscles. However, the maintenance of the relative expression of slow MHC protein is independent of neuromuscular activity in mice. skeletal muscle; tenotomy; force; slow myosin heavy chain; power; velocity of shortening; oxidative capacity; atrophy NEUROMUSCULAR ACTIVITY, INCLUDING both the neural and mechanical aspects, plays an important role in skeletal muscle physiology. It is now well established that increased chronic neuromuscular activity (physical training and electrical stimulation) induces beneficial adaptations in both muscle structure and function (for review, Refs. 23, 46). Moreover, there is a very large body of information showing that reduced neuromuscular activity (i.e., denervation, spinal cord isolation, disuse) causes important impairments in muscle function (for review, Refs. 20,41). For example, a reduction or the elimination of neural input results in muscle atrophy. Denervated slow muscles produce less maximal force and power, and the kinetics of the twitch is slower. This is accompanied by a reduction in oxidative capacity and a decrease in the relative expression of slow myosin heavy chain (MHC-1) protein (for review, Refs. 41, 53). However, it should be noted that most of this experimental data is derived from experiments on rats.MHC-1 protein is one of the major contractile proteins and is important for muscle function. A high level of MHC-1 expression in skeletal m...

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“…By contrast there was a significant decrease in the number of macrophages in the soleus muscles of hSOD1 G93A mice lacking C5aR1 (n = 3, ***p < 0.001; Figure 16B). Interestingly, the number of macrophages in soleus muscles of hSOD1 G93A mice was much lower than the number of macrophages in tibialis anterior muscles of hSOD1 G93A mice, which supports other studies that showed fast-twitch muscles are preferentially affected in hSOD1 G93A mice when compared to slow-twitch muscles (Figure 16) (Frey et al, 2000, Atkin et al, 2005. This idea was also supported by the quantification of T helper cells, where no significant differences of T helper cell numbers were observed in soleus muscles across wild-type, hSOD1 G93A , and hSOD1 G93A x C5aR1 -/-mice during ALS disease progression, but the numbers of T helper cells in tibialis anterior muscles of hSOD1 G93A muscles were markedly higher than their counterparts in soleus muscles (Figure 17).…”

Section: Hsod1supporting

confidence: 87%

“…Therefore, I defined the soleus muscle as a slow-twitch muscle in the present study (Barclay et al, 1993, Atkin et al, 2005, Hegedus et al, 2007.…”

Section: Muscle Denervation In Als Mouse Modelsmentioning

confidence: 99%

“…It has been demonstrated that fast-twitch muscle fibres are preferentially affected in ALS (Frey et al, 2000, Atkin et al, 2005, Pun et al, 2006. As massive invasions of immune cells were shown in tibialis anterior muscles that are vulnerable in ALS, this raises the question of the extent of immune cells invasions into muscles that are less vulnerable in ALS, like slow-twitch soleus muscles.…”

Section: Hsod1mentioning

confidence: 99%

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Role of complement in ALS: regulating peripheral immune cells in skeletal muscle of hSOD1G93A mouse model of ALS

Wang¹

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Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disease. It is characterised by progressive loss of motor neurons and muscle atrophy. Recently, mounting evidence has suggested that complement, part of the innate immune system, is involved in the pathogenesis of ALS in both human patients and in animal models.Activation of complement in the central nervous system (CNS) has been well defined and has been proved to be critical to the death of motor neurons. However, less is known about the roles of complement in the skeletal muscle during the ALS disease progression.The initial aim of this study was to examine the complement activation in skeletal muscle of hSOD1 G93A mice, a well-characterised ALS animal model. Expressions of major complement factors (C1qB, C3, factor B, C4, C5, C5aR1, and C3aR) and regulators (CD55, CD59) were determined, and shown to be significantly elevated in the skeletal muscle of hSOD1 G93A when compared to wide-type (WT) mice as disease progressed,suggesting that complement activation in the skeletal muscle of hSOD1 G93A mice is achieved through classical and possibly other complement cascades. In addition, expression levels of C5aR1 and C3aR, receptors for complement peptides C5a and C3a respectively, were also increased. Immunolocalisation studies shows that C5aR1 and C3aR are expressed on invading immune cells, CD11b + macrophage and CD4 + helper T cells, in skeletal muscle of hSOD1 G93A mice.The second aim of this study was to investigate the physiological roles of complement signalling in regulating immune cell migration in skeletal muscle of hSOD1 G93A mice.Massive invasions of macrophage and helper T cell were observed in tibialis anterior muscles of hSOD1 G93A mice when compared to age-matched wild-type mice. These infiltrations were remarkably attenuated in hSOD1 G93A mice lacking either C5aR1 or C3aR.By contrast, there was significantly less immune cell invasion into soleus muscles of hSOD1 G93A mice, but like for the tibialis anterior muscle, this invasion is significantly greater when compared to soleus muscles from age-matched wild-type mice, and attenuated in soleus muscle from hSOD1 G93A mice lacking either C5aR1 or C3aR. The soleus muscle, predominantly a slow-twitch muscle, is less vulnerable to denervation in hSOD1 G93A mice. Taken together, these results indicate that C5a-C5aR1 and C3a-C3aR signalling regulates the migration of immune cells into the skeletal muscle during ALS disease progression, and the extent of immune cell influx is related to physiological ii function of skeletal muscle.In summary, I have shown activation of the complement system in the skeletal muscle of hSOD1 G93A ALS mouse model, suggesting a role of complement C5a-C5aR1 and C3a-C3aR signalling in recruiting immune cells into skeletal muscle during disease progression.As skeletal muscle is the prime target for ALS, these findings may promote skeletal muscle as a therapeutic target for effects of complement factors in ALS treatment.iii

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Properties of slow- and fast-twitch muscle fibres in a mouse model of amyotrophic lateral sclerosis

Cited by 73 publications

References 40 publications

Species-dependent neuropathology in transgenic SOD1 pigs

Species-dependent neuropathology in transgenic SOD1 pigs

Slow myosin heavy chain expression in the absence of muscle activity

Role of complement in ALS: regulating peripheral immune cells in skeletal muscle of hSOD1G93A mouse model of ALS

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