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New pathobiochemical insights into dystrophinopathy from the proteomics of senescent mdx mouse muscle.

Holland A, Dowling P, Ohlendieck K - Front Aging Neurosci (2014)

Bottom Line: The idea that aging exacerbates the dystrophic mdx phenotype, as previously indicated by a large number of biochemical and cell biological studies, was clearly confirmed by comparative muscle proteomics.Here we outline recent findings of age-dependent changes in the dystrophin-deficient muscle proteome and contrast these results with the previously established proteomic profile of sarcopenic muscle.Besides comparable perturbations of various biochemical functions, especially striking are similarities in the cellular stress response associated with a drastic up-regulation of small αB-crystallin-like heat shock proteins.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, National University of Ireland Maynooth, Ireland.

ABSTRACT
Primary abnormalities in the dystrophin gene cause X-linked muscular dystrophy, a highly progressive muscle wasting disorder of childhood. A spontaneous animal model of Duchenne muscular dystrophy is the mdx mouse, which presents a highly interesting phenotype that exhibits considerable variations in the degree of fiber degeneration in different subtypes of muscles. The idea that aging exacerbates the dystrophic mdx phenotype, as previously indicated by a large number of biochemical and cell biological studies, was clearly confirmed by comparative muscle proteomics. Here we outline recent findings of age-dependent changes in the dystrophin-deficient muscle proteome and contrast these results with the previously established proteomic profile of sarcopenic muscle. Besides comparable perturbations of various biochemical functions, especially striking are similarities in the cellular stress response associated with a drastic up-regulation of small αB-crystallin-like heat shock proteins. Hence, the comparison of large-scale proteomic data sets of natural muscle aging with dystrophic sarcopenia promises to shed light on the differential effect of sarcopenia of old age vs. senescent abnormalities on a mutant dystrophic background.

No MeSH data available.


Related in: MedlinePlus

Age-related progression of pathophysiological abnormalities in dystrophin-deficient muscle.
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Figure 1: Age-related progression of pathophysiological abnormalities in dystrophin-deficient muscle.

Mentions: The combination of large-scale protein separation techniques, such as two-dimensional gel electrophoresis and advanced liquid chromatography, and high-resolution mass spectrometry enable ultra-sensitive proteomic workflows (Altelaar and Heck, 2012). Over the last decade, mass spectrometry-based proteomics has been applied to studying the dystrophin-glycoprotein complex and the many downstream effects of dystrophin deficiency in muscular dystrophy (for review see, Holland et al., 2013a). Many of these investigations have focused on crude cellular extracts from the mdx mouse model of dystrophinopathy and the flow chart of Figure 1 outlines that the dystrophic mdx phenotype is characterized initially by moderate changes in the muscle tissue proteome, followed by considerably more severe proteome-wide changes in aged muscles on a mutant dystrophic background. The proteomic profiling of mildly dystrophic muscle subtypes revealed only very few changes in extraocular and interosseus muscles (Lewis and Ohlendieck, 2010; Carberry et al., 2013a). Segmental necrosis in moderately affected young mdx leg muscles was shown to be associated with changes in nucleotide metabolism (Ge et al., 2003) and generally perturbed muscle protein expression levels (Gardan-Salmon et al., 2011). Considerable changes in the degree and number of proteins was revealed by the fluorescence two-dimensional difference in-gel electrophoretic analysis of the adult mdx diaphragm muscle, which exhibits a variety of alterations in proteins involved in muscle contraction, ion homeostasis, nucleotide metabolism, the cellular stress response, energy metabolism and sarcolemmal signaling (Doran et al., 2006). Hence, dystrophin deficiency and the resulting collapse of the linkage between the intracellular actin cytoskeleton and the basal lamina triggers a variety of downstream modifications in muscular dystrophy.


New pathobiochemical insights into dystrophinopathy from the proteomics of senescent mdx mouse muscle.

Holland A, Dowling P, Ohlendieck K - Front Aging Neurosci (2014)

Age-related progression of pathophysiological abnormalities in dystrophin-deficient muscle.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4042888&req=5

Figure 1: Age-related progression of pathophysiological abnormalities in dystrophin-deficient muscle.
Mentions: The combination of large-scale protein separation techniques, such as two-dimensional gel electrophoresis and advanced liquid chromatography, and high-resolution mass spectrometry enable ultra-sensitive proteomic workflows (Altelaar and Heck, 2012). Over the last decade, mass spectrometry-based proteomics has been applied to studying the dystrophin-glycoprotein complex and the many downstream effects of dystrophin deficiency in muscular dystrophy (for review see, Holland et al., 2013a). Many of these investigations have focused on crude cellular extracts from the mdx mouse model of dystrophinopathy and the flow chart of Figure 1 outlines that the dystrophic mdx phenotype is characterized initially by moderate changes in the muscle tissue proteome, followed by considerably more severe proteome-wide changes in aged muscles on a mutant dystrophic background. The proteomic profiling of mildly dystrophic muscle subtypes revealed only very few changes in extraocular and interosseus muscles (Lewis and Ohlendieck, 2010; Carberry et al., 2013a). Segmental necrosis in moderately affected young mdx leg muscles was shown to be associated with changes in nucleotide metabolism (Ge et al., 2003) and generally perturbed muscle protein expression levels (Gardan-Salmon et al., 2011). Considerable changes in the degree and number of proteins was revealed by the fluorescence two-dimensional difference in-gel electrophoretic analysis of the adult mdx diaphragm muscle, which exhibits a variety of alterations in proteins involved in muscle contraction, ion homeostasis, nucleotide metabolism, the cellular stress response, energy metabolism and sarcolemmal signaling (Doran et al., 2006). Hence, dystrophin deficiency and the resulting collapse of the linkage between the intracellular actin cytoskeleton and the basal lamina triggers a variety of downstream modifications in muscular dystrophy.

Bottom Line: The idea that aging exacerbates the dystrophic mdx phenotype, as previously indicated by a large number of biochemical and cell biological studies, was clearly confirmed by comparative muscle proteomics.Here we outline recent findings of age-dependent changes in the dystrophin-deficient muscle proteome and contrast these results with the previously established proteomic profile of sarcopenic muscle.Besides comparable perturbations of various biochemical functions, especially striking are similarities in the cellular stress response associated with a drastic up-regulation of small αB-crystallin-like heat shock proteins.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, National University of Ireland Maynooth, Ireland.

ABSTRACT
Primary abnormalities in the dystrophin gene cause X-linked muscular dystrophy, a highly progressive muscle wasting disorder of childhood. A spontaneous animal model of Duchenne muscular dystrophy is the mdx mouse, which presents a highly interesting phenotype that exhibits considerable variations in the degree of fiber degeneration in different subtypes of muscles. The idea that aging exacerbates the dystrophic mdx phenotype, as previously indicated by a large number of biochemical and cell biological studies, was clearly confirmed by comparative muscle proteomics. Here we outline recent findings of age-dependent changes in the dystrophin-deficient muscle proteome and contrast these results with the previously established proteomic profile of sarcopenic muscle. Besides comparable perturbations of various biochemical functions, especially striking are similarities in the cellular stress response associated with a drastic up-regulation of small αB-crystallin-like heat shock proteins. Hence, the comparison of large-scale proteomic data sets of natural muscle aging with dystrophic sarcopenia promises to shed light on the differential effect of sarcopenia of old age vs. senescent abnormalities on a mutant dystrophic background.

No MeSH data available.


Related in: MedlinePlus