Mitochondrial dysfunction is an early consequence of partial or complete&amp;nbsp;dystrophin loss in&amp;nbsp;mdx&amp;nbsp;mice.

Moore, Timothy M.; Lin, Athena W.; Strumwasser, Alexander R.; Cory, Kevin; Whitney, Kate; Ho, Theodore; Ho, Tammy Szu-Yu; Lee, Joseph L.; Rucker, Daniel H.; Nguyen, Christina Q.; Yackly, Aidan; Mahata, Sushil K.; Wanagat, Jonathan; Stiles, Linsey; Turcotte, Lorraine P.; Crosbie, Rachelle H.; Zhou, Zhenqi

doi:10.21203/rs.2.23961/v1

Cited by 4 publications

(5 citation statements)

References 78 publications

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“…We would like to thank the UCLA Division of Laboratory Animal Medicine and Katie Moore for assisting us in animal welfare and data collection, respectively. This manuscript has been released as a pre-print at https://www.researchsquare.com/article/rs-14522/ v1 (Moore et al, 2020).…”

Section: Acknowledgmentsmentioning

confidence: 99%

Mitochondrial Dysfunction Is an Early Consequence of Partial or Complete Dystrophin Loss in mdx Mice

et al. 2020

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Duchenne muscular dystrophy (DMD) is characterized by rapid wasting of skeletal muscle. Mitochondrial dysfunction is a well-known pathological feature of DMD. However, whether mitochondrial dysfunction occurs before muscle fiber damage in DMD pathology is not well known. Furthermore, the impact upon heterozygous female mdx carriers (mdx/+), who display dystrophin mosaicism, has received little attention. We hypothesized that dystrophin deletion leads to mitochondrial dysfunction, and that this may occur before myofiber necrosis. As a secondary complication to mitochondrial dysfunction, we also hypothesized metabolic abnormalities prior to the onset of muscle damage. In this study, we detected aberrant mitochondrial morphology, reduced cristae number, and large mitochondrial vacuoles from both male and female mdx mice prior to the onset of muscle damage. Furthermore, we systematically characterized mitochondria during disease progression starting before the onset of muscle damage, noting additional changes in mitochondrial DNA copy number and regulators of mitochondrial size. We further detected mild metabolic and mitochondrial impairments in female mdx carrier mice that were exacerbated with high-fat diet feeding. Lastly, inhibition of the strong autophagic program observed in adolescent mdx male mice via administration of the autophagy inhibitor leupeptin did not improve skeletal muscle pathology. These results are in line with previous data and suggest that before the onset of myofiber necrosis, mitochondrial and metabolic abnormalities are present within the mdx mouse.

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Section: Acknowledgmentsmentioning

confidence: 99%

Mitochondrial Dysfunction Is an Early Consequence of Partial or Complete Dystrophin Loss in mdx Mice

et al. 2020

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“…Disrupted mitochondrial function and metabolism are associated with Duchenne muscular dystrophy (DMD) (1,2,30). In mouse models of DMD (mdx mice), disrupted mitochondrial metabolism was observed early on in disease progression, suggesting disrupted mitochondrial metabolism may contribute to DMD pathophysiology (2).…”

Section: Discussionmentioning

confidence: 99%

“…These stimuli elicit dynamic changes in cellular energy demand and substrate availability that require cellular adaptation. Disrupted mitochondrial function can contribute to a failure in adaptation and is associated with several human diseases including muscular dystrophies and sarcopeniaskeletal muscle disorders that are associated with decreased muscle mass and mitochondrial function (1)(2)(3)(4). Studies have focused on identifying therapeutic targets to enhance mitochondrial function and thus improve adaptability in human disease states.…”

Section: Introductionmentioning

confidence: 99%

Site-1 Protease inhibits mitochondrial metabolism by controlling the TGF-β target gene MSS51

Mousa

Vuppaladhadiam

Kelly

et al. 2022

Preprint

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The mitochondrial response to changes in cellular energy demand is necessary for cellular adaptation and organ function. Many genes are essential in orchestrating this response, including the transforming growth factor (TGFβ) target gene MSS51, which is an inhibitor of skeletal muscle mitochondrial metabolism. Despite the potential importance of MSS51 in the pathophysiology of obesity and musculoskeletal disease, how MSS51 is regulated is not entirely understood. Site-1 Protease (S1P) is a Golgi-resident protease that is a key activator of several transcription factors required for cellular adaptation. However, the role of S1P in muscle and mitochondrial function are unknown. Here, we identify S1P as a negative regulator of muscle mass and mitochondrial metabolism. Disruption of S1P in mouse skeletal muscle and cultured myofibers leads to a reduction in MSS51 expression, increased muscle mass, and increased mitochondrial oxygen consumption. The effects of S1P deficiency on mitochondrial activity are counteracted by overexpressing MSS51, suggesting that S1P inhibits mitochondrial metabolism by regulating the expression of MSS51. Furthermore, S1P suppression enhances TGFβ signaling via the AKT pathway, potentially explaining muscle hypertrophy in S1P deficient mice. The discovery of S1P as a regulator of mitochondrial metabolism and muscle mass expands our understanding of TGF-β signaling and suggests this protease could be a target for therapeutic intervention in muscle.

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“…S4C). Previous reports indicate that mitochondrial dysfunction precedes both skeletal and cardiac muscle impairment in DMD [87][88][89], making it an area of continued focus for future DMD-related studies.…”

Section: Discussionmentioning

confidence: 99%

A Deep Redox Proteome Profiling Workflow and Its Application to Skeletal Muscle of a Duchene Muscular Dystrophy Model

Day

Zhang

Gaffrey

et al. 2022

Preprint

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Perturbation to the redox state accompanies many diseases and its effects are viewed through oxidation of biomolecules, including proteins, lipids, and nucleic acids. The thiol groups of protein cysteine residues undergo an array of redox post-translational modifications (PTMs) that are important for regulation of protein and pathway function. To better understand what proteins are redox regulated following a perturbation, it is important to be able to comprehensively profile protein thiol oxidation at the proteome level. Herein, we report a deep redox proteome profiling workflow and demonstrate its application in measuring the changes in thiol oxidation along with global protein expression in skeletal muscle from mdx mice, a model of Duchenne Muscular Dystrophy (DMD). In depth coverage of the thiol proteome was achieved with >18,000 Cys sites from 5608 proteins in muscle being quantified. Compared to the control group, mdx mice exhibit markedly increased thiol oxidation, where ~2% shift in the median oxidation occupancy was observed. Pathway analysis for the redox data revealed that coagulation system and immune-related pathways were among the most susceptible to increased thiol oxidation in mdx mice, whereas protein abundance changes were more enriched in pathways associated with bioenergetics. This study illustrates the importance of deep redox profiling in gaining a greater insight into oxidative stress regulation and pathways/processes being perturbed in an oxidizing environment.

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Mitochondrial dysfunction is an early consequence of partial or complete dystrophin loss in mdx mice.

Cited by 4 publications

References 78 publications

Mitochondrial Dysfunction Is an Early Consequence of Partial or Complete Dystrophin Loss in mdx Mice

Mitochondrial Dysfunction Is an Early Consequence of Partial or Complete Dystrophin Loss in mdx Mice

Site-1 Protease inhibits mitochondrial metabolism by controlling the TGF-β target gene MSS51

A Deep Redox Proteome Profiling Workflow and Its Application to Skeletal Muscle of a Duchene Muscular Dystrophy Model

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