Rapid, redox-mediated mechanical susceptibility of the cortical microtubule lattice in skeletal muscle

Nelson, D'anna M.; Fasbender, Elizabeth K.; Jakubiak, Margurite C.; Lindsay, Angus; Lowe, Dawn A.; Ervasti, James M.

doi:10.1016/j.redox.2020.101730

Cited by 14 publications

(10 citation statements)

References 70 publications

(134 reference statements)

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“…Our group, and others [28][29][30][31] , have implicated disease dependent MT alterations as negative disease modifiers in adult mdx mice with advanced pathology. Western blot profiling of gastrocnemius muscle from 4 wk mdx mice finds no significant alteration in the expression of tubulin protein, its modification by acetylation (acetyl), nor the abundance of gp91phox, the catalytic subunit of the reactive oxygen species (ROS) producing enzyme, Nox2.…”

Section: Young MDX Mice Exhibit Functional Deficits and Microtubule A...mentioning

confidence: 83%

Myofibrillar malformations that arise in mdx muscle fibers are driven by detyrosinated microtubules

Harriot

Morris

Venegas

et al. 2023

Preprint

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In Duchenne muscular dystrophy (DMD), alterations in the myofibrillar structure of skeletal muscle fibers that impair contractile function and increase injury susceptibility arise as a consequence of dystrophic pathology. In murine DMD (mdx), myofibrillar alterations are abundant in advanced pathology (>4 months), an age where we formerly established the densification of microtubules (MTs) post-translationally modified by detyrosination (deTyr-MTs) as a negative disease modifier. Given the essential role of MTs in myofibrillar growth, maintenance, and repair, we examined the increased abundance of deTyr-MTs as a potential mechanism for these myofibrillar alterations. Here we find increased levels of deTyr-MTs as an early event in dystrophic pathology (4 weeks) with no evidence of myofibrillar alterations. At 16 weeks, we find the level of deTyr-MTs is significantly increased and co-localized to areas of myofibrillar malformation. Profiling the enzyme complexes responsible for deTyr-tubulin, we found vasohibin 2 (VASH2) significantly elevated in the mdx muscle at 4 and 16 wks. Genetically increasing VASH2 expression in 4 wk, wild-type mice we now find densified deTyr-MTs that co-segregate with myofibrillar malformations similar to those in the 16 wk mdx. Given that no changes were identified in fibers expressing EGFP as a control, we conclude that disease altered microtubules underscore the altered myofibrillar structure in dystrophic skeletal muscle fibers.

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Section: Young MDX Mice Exhibit Functional Deficits and Microtubule A...mentioning

confidence: 83%

Myofibrillar malformations that arise in mdx muscle fibers are driven by detyrosinated microtubules

Harriot

Morris

Venegas

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…16 The data further suggest that overexpressing a nearly full length dystrophin chimera in skeletal muscle of mdx mice does not affect the global or skeletal muscle BH 4 to BH 2 ratio, but that this ratio does not seem to impact global oxidative stress (biopterin [Figure 3], isoxanthopterin and ortho-tyrosine 16 ) in a mouse model that is rescued for most skeletal muscle phenotypes. 42,52 However, while dystrophin overexpression could not rescue the BH 4 to BH 2 ratio in urine or skeletal muscle, BH 4 supplementation did elevate this ratio in skeletal muscle in mdx mice.…”

Section: Discussionmentioning

confidence: 97%

Tetrahydrobiopterin synthesis and metabolism is impaired in dystrophin‐deficient mdx mice and humans

et al. 2021

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Aim Loss of dystrophin causes oxidative stress and affects nitric oxide synthase‐mediated vascular function in striated muscle. Because tetrahydrobiopterin is an antioxidant and co‐factor for nitric oxide synthase, we tested the hypothesis that tetrahydrobiopterin would be low in mdx mice and humans deficient for dystrophin. Methods Tetrahydrobiopterin and its metabolites were measured at rest and in response to exercise in Duchenne and Becker muscular dystrophy patients, age‐matched male controls as well as wild‐type, mdx and mdx mice transgenically overexpressing skeletal muscle‐specific dystrophins. Mdx mice were also supplemented with tetrahydrobiopterin and pathophysiology was assessed. Results Duchenne muscular dystrophy patients had lower urinary dihydrobiopterin + tetrahydrobiopterin/specific gravity1.020 compared to unaffected age‐matched males and Becker muscular dystrophy patients. Mdx mice had low urinary and skeletal muscle dihydrobiopterin + tetrahydrobiopterin compared to wild‐type mice. Overexpression of dystrophins that localize neuronal nitric oxide synthase restored dihydrobiopterin + tetrahydrobiopterin in mdx mice to wild‐type levels while utrophin overexpression did not. Mdx mice and Duchenne muscular dystrophy patients did not increase tetrahydrobiopterin during exercise and in mdx mice tetrahydrobiopterin deficiency was likely because of lower levels of sepiapterin reductase in skeletal muscle. Tetrahydrobiopterin supplementation improved skeletal muscle strength, resistance to fatiguing and injurious contractions in vivo, increased utrophin and capillary density of skeletal muscle and lowered cardiac muscle fibrosis and left ventricular wall thickness in mdx mice. Conclusion These data demonstrate that impaired tetrahydrobiopterin synthesis is associated with dystrophin loss and treatment with tetrahydrobiopterin improves striated muscle histopathology and skeletal muscle function in mdx mice.

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“…A related possibility might be increased production of reactive oxygen species (ROS). Hence, a ROS‐dependent loss of transverse microtubules has been described in β and γ‐actin −/− muscles, partly depedendent on NOX2 (Nelson et al, 2020). Both NOX2 and other ROS sources such as mitochondria have been implicated in the development of insulin‐resistance, with considerable cross‐talk known to occur between the two (Henríquez‐Olguín et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Gene deletion of γ‐actin impairs insulin‐stimulated skeletal muscle glucose uptake in growing mice but not in mature adult mice

Knudsen

Madsen

et al. 2022

Physiological Reports

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The cortical cytoskeleton, consisting of the cytoplasmic actin isoforms β and/or γ‐actin, has been implicated in insulin‐stimulated GLUT4 translocation and glucose uptake in muscle and adipose cell culture. Furthermore, transgenic inhibition of multiple actin‐regulating proteins in muscle inhibits insulin‐stimulated muscle glucose uptake. The current study tested if γ‐actin was required for insulin‐stimulated glucose uptake in mouse skeletal muscle. Based on our previously reported age‐dependent phenotype in muscle‐specific β‐actin gene deletion (−/−) mice, we included cohorts of growing 8–14 weeks old and mature 18–32 weeks old muscle‐specific γ‐actin−/− mice or wild‐type littermates. In growing mice, insulin significantly increased the glucose uptake in slow‐twitch oxidative soleus and fast‐twitch glycolytic EDL muscles from wild‐type mice, but not γ‐actin−/−. In relative values, the maximal insulin‐stimulated glucose uptake was reduced by ~50% in soleus and by ~70% in EDL muscles from growing γ‐actin−/− mice compared to growing wild‐type mice. In contrast, the insulin‐stimulated glucose uptake responses in mature adult γ‐actin−/− soleus and EDL muscles were indistinguishable from the responses in wild‐type muscles. Mature adult insulin‐stimulated phosphorylations on Akt, p70S6K, and ULK1 were not significantly affected by genotype. Hence, insulin‐stimulated muscle glucose uptake shows an age‐dependent impairment in young growing but not in fully grown γ‐actin−/− mice, bearing phenotypic resemblance to β‐actin−/− mice. Overall, γ‐actin does not appear required for insulin‐stimulated muscle glucose uptake in adulthood. Furthermore, our data emphasize the need to consider the rapid growth of young mice as a potential confounder in transgenic mouse phenotyping studies.

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Rapid, redox-mediated mechanical susceptibility of the cortical microtubule lattice in skeletal muscle

Cited by 14 publications

References 70 publications

Myofibrillar malformations that arise in mdx muscle fibers are driven by detyrosinated microtubules

Myofibrillar malformations that arise in mdx muscle fibers are driven by detyrosinated microtubules

Tetrahydrobiopterin synthesis and metabolism is impaired in dystrophin‐deficient mdx mice and humans

Gene deletion of γ‐actin impairs insulin‐stimulated skeletal muscle glucose uptake in growing mice but not in mature adult mice

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