Impaired autophagy correlates with golden retriever muscular dystrophy phenotype

Stoughton, William B.; Lǐ, Jiànróng; Balog-Alvarez, Cindy; Kornegay, Joe N.

doi:10.1002/mus.26121

Cited by 8 publications

(4 citation statements)

References 52 publications

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“…Previous studies have shown that defective autophagy and disorganized MT network play an important role in disease progression and contributes to DMD pathogenesis before the manifestation of severe phenotypes 11, 48–51 . Therefore, reverting autophagic dysfunction could be an efficient approach to slow the onset of disease progression and improve the muscle function in DMD patients.…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase 6 inhibition promotes microtubule acetylation and facilitates autophagosome-lysosome fusion in dystrophin-deficient mdx mice

Agrawal

Clayton

Cavazos

et al. 2022

Preprint

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Duchenne Muscular Dystrophy (DMD) is a severe X-linked genetic disorder. Defective autophagy and disorganized microtubule network contributes to DMD pathogenesis, yet the mechanisms by which microtubule alterations regulate autophagy remain elusive. We show decreased acetylated α-tubulin and enhanced histone deacetylase (HDAC6) expression in mdx mice. Pharmacological inhibition of HDAC6 increases tubulin acetylation and enhances Q-SNARE complex formation, leading to improved autophagosome-lysosome fusion. HDAC6 inhibition reduces apoptosis, inflammation, muscle damage and prevents contraction induced force loss. HDAC6 inhibition restores peroxiredoxin (PrxII) by increasing its acetylation and protecting it from hyper-oxidation, hence modulating intracellular redox status in mdx mice. Genetic inhibition of Nox2 activity in mdx mice promotes autophagosome maturation. Our data highlight that autophagy is differentially regulated by redox and acetylation in mdx mice. By restoring tubulin acetylation HDAC6 inhibition enhances autophagy, ameliorates the dystrophic phenotype and improves muscle function, suggesting a potential therapeutic target for treating DMD.

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Section: Discussionmentioning

confidence: 99%

Histone deacetylase 6 inhibition promotes microtubule acetylation and facilitates autophagosome-lysosome fusion in dystrophin-deficient mdx mice

Agrawal

Clayton

Cavazos

et al. 2022

Preprint

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“…The defect is not restricted to muscle; indeed, dystrophic thymocytes also show altered autophagic flux contributing to dysregulated thymocyte differentiation and abnormal T-cell development [58]. Moreover, autophagy defects can be extended to more severe models of DMD, such as golden retriever muscular dystrophy (GRMD) in which impaired autophagy correlates with disease severity [59], and D2-mdx mice [60].…”

Section: Autophagy and Mitophagymentioning

confidence: 99%

Mitochondria and Reactive Oxygen Species: The Therapeutic Balance of Powers for Duchenne Muscular Dystrophy

Casati,

Cervia,

Roux-Biejat

et al. 2024

Cells

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Duchenne muscular dystrophy (DMD) is a genetic progressive muscle-wasting disorder that leads to rapid loss of mobility and premature death. The absence of functional dystrophin in DMD patients reduces sarcolemma stiffness and increases contraction damage, triggering a cascade of events leading to muscle cell degeneration, chronic inflammation, and deposition of fibrotic and adipose tissue. Efforts in the last decade have led to the clinical approval of novel drugs for DMD that aim to restore dystrophin function. However, combination therapies able to restore dystrophin expression and target the myriad of cellular events found impaired in dystrophic muscle are desirable. Muscles are higher energy consumers susceptible to mitochondrial defects. Mitochondria generate a significant source of reactive oxygen species (ROS), and they are, in turn, sensitive to proper redox balance. In both DMD patients and animal models there is compelling evidence that mitochondrial impairments have a key role in the failure of energy homeostasis. Here, we highlighted the main aspects of mitochondrial dysfunction and oxidative stress in DMD and discussed the recent findings linked to mitochondria/ROS-targeted molecules as a therapeutic approach. In this respect, dual targeting of both mitochondria and redox homeostasis emerges as a potential clinical option in DMD.

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“…1 B ), DMD fibers, like healthy SMFs, can repair sarcolemma tears. Ca 2+ -mediated exocytosis seals the tear; endocytosis then retrieves excess bilayer, though mdx- fibers’ impaired autophagy impedes subsequent reprocessing ( McNeil and Steinhardt, 2003 ; Corrotte et al, 2013 ; Andrews et al, 2014 ; Barthélémy et al, 2018 ; Stoughton et al, 2018 ; Call and Nichenko, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

The Donnan-dominated resting state of skeletal muscle fibers contributes to resilience and longevity in dystrophic fibers

Morris

Wheeler

Joós

2021

Journal of General Physiology

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Duchenne muscular dystrophy (DMD) is an X-linked dystrophin-minus muscle-wasting disease. Ion homeostasis in skeletal muscle fibers underperforms as DMD progresses. But though DMD renders these excitable cells intolerant of exertion, sodium overloaded, depolarized, and spontaneously contractile, they can survive for several decades. We show computationally that underpinning this longevity is a strikingly frugal, robust Pump-Leak/Donnan (P-L/D) ion homeostatic process. Unlike neurons, which operate with a costly “Pump-Leak–dominated” ion homeostatic steady state, skeletal muscle fibers operate with a low-cost “Donnan-dominated” ion homeostatic steady state that combines a large chloride permeability with an exceptionally small sodium permeability. Simultaneously, this combination keeps fiber excitability low and minimizes pump expenditures. As mechanically active, long-lived multinucleate cells, skeletal muscle fibers have evolved to handle overexertion, sarcolemmal tears, ischemic bouts, etc.; the frugality of their Donnan dominated steady state lets them maintain the outsized pump reserves that make them resilient during these inevitable transient emergencies. Here, P-L/D model variants challenged with DMD-type insult/injury (low pump-strength, overstimulation, leaky Nav and cation channels) show how chronic “nonosmotic” sodium overload (observed in DMD patients) develops. Profoundly severe DMD ion homeostatic insult/injury causes spontaneous firing (and, consequently, unwanted excitation–contraction coupling) that elicits cytotoxic swelling. Therefore, boosting operational pump-strength and/or diminishing sodium and cation channel leaks should help extend DMD fiber longevity.

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Impaired autophagy correlates with golden retriever muscular dystrophy phenotype

Abstract: Our data suggest that autophagy is impaired in certain GRMD muscles. Differential GRMD CS involvement emphasizes that therapeutic modulation of autophagy could require specific muscle targeting. Muscle Nerve 58: 418-426, 2018.

Cited by 8 publications

References 52 publications

Histone deacetylase 6 inhibition promotes microtubule acetylation and facilitates autophagosome-lysosome fusion in dystrophin-deficient mdx mice

Histone deacetylase 6 inhibition promotes microtubule acetylation and facilitates autophagosome-lysosome fusion in dystrophin-deficient mdx mice

Mitochondria and Reactive Oxygen Species: The Therapeutic Balance of Powers for Duchenne Muscular Dystrophy

The Donnan-dominated resting state of skeletal muscle fibers contributes to resilience and longevity in dystrophic fibers

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