27 results on '"Mázala, Davi A. G."'
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2. Absence of the Z-disc protein α-actinin-3 impairs the mechanical stability of Actn3KO mouse fast-twitch muscle fibres without altering their contractile properties or twitch kinetics
- Author
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Haug, Michael, Reischl, Barbara, Nübler, Stefanie, Kiriaev, Leonit, Mázala, Davi A. G., Houweling, Peter J., North, Kathryn N., Friedrich, Oliver, and Head, Stewart I.
- Published
- 2022
- Full Text
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3. Altered muscle niche contributes to myogenic deficit in the D2-mdx model of severe DMD
- Author
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Mázala, Davi A. G., primary, Hindupur, Ravi, additional, Moon, Young Jae, additional, Shaikh, Fatima, additional, Gamu, Iteoluwakishi H., additional, Alladi, Dhruv, additional, Panci, Georgiana, additional, Weiss-Gayet, Michèle, additional, Chazaud, Bénédicte, additional, Partridge, Terence A., additional, Novak, James S., additional, and Jaiswal, Jyoti K., additional
- Published
- 2023
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4. Practical Nutrition Guidelines for Individuals with Duchenne Muscular Dystrophy
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Davidson, Zoe E., Rodden, Greg, Mázala, Davi A. G., Moore, Cynthia, Papillon, Carol, Hasemann, Angela J., Truby, Helen, Grange, Robert W., Turksen, Kursad, Series editor, and Childers, Martin K., editor
- Published
- 2016
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5. Altered muscle niche contributes to myogenic deficit in the D2-mdxmodel of severe DMD
- Author
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Mázala, Davi A. G., primary, Hindupur, Ravi, additional, Moon, Young Jae, additional, Shaikh, Fatima, additional, Gamu, Iteoluwakishi H., additional, Alladi, Dhruv, additional, Panci, Georgiana, additional, Weiss-Gayet, Michèle, additional, Chazaud, Bénédicte, additional, Partridge, Terence A., additional, Novak, James S., additional, and Jaiswal, Jyoti K., additional
- Published
- 2023
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- View/download PDF
6. Practical Nutrition Guidelines for Individuals with Duchenne Muscular Dystrophy
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Davidson, Zoe E., primary, Rodden, Greg, additional, Mázala, Davi A. G., additional, Moore, Cynthia, additional, Papillon, Carol, additional, Hasemann, Angela J., additional, Truby, Helen, additional, and Grange, Robert W., additional
- Published
- 2015
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7. Human muscle stem cells are refractory to aging
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Novak, James S., primary, Mázala, Davi A. G., additional, Nearing, Marie, additional, Hindupur, Ravi, additional, Uapinyoying, Prech, additional, Habib, Nayab F., additional, Dickson, Tessa, additional, Ioffe, Olga B., additional, Harris, Brent T., additional, Fidelia‐Lambert, Marie N., additional, Rossi, Christopher T., additional, Hill, D. Ashely, additional, Wagner, Kathryn R., additional, Hoffman, Eric P., additional, and Partridge, Terence A., additional
- Published
- 2021
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8. Coping with the calcium overload caused by cell injury: ER to the rescue
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Chandra, Goutam, primary, Mázala, Davi A. G., additional, and Jaiswal, Jyoti K., additional
- Published
- 2021
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9. Calcium dysregulation, functional calpainopathy, and endoplasmic reticulum stress in sporadic inclusion body myositis
- Author
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Amici, David R., primary, Pinal-Fernandez, Iago, additional, Mázala, Davi A. G., additional, Lloyd, Thomas E., additional, Corse, Andrea M., additional, Christopher-Stine, Lisa, additional, Mammen, Andrew L., additional, and Chin, Eva R., additional
- Published
- 2017
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10. NAD + repletion improves muscle function in muscular dystrophy and counters global PARylation
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Ryu, Dongryeol, primary, Zhang, Hongbo, additional, Ropelle, Eduardo R., additional, Sorrentino, Vincenzo, additional, Mázala, Davi A. G., additional, Mouchiroud, Laurent, additional, Marshall, Philip L., additional, Campbell, Matthew D., additional, Ali, Amir Safi, additional, Knowels, Gary M., additional, Bellemin, Stéphanie, additional, Iyer, Shama R., additional, Wang, Xu, additional, Gariani, Karim, additional, Sauve, Anthony A., additional, Cantó, Carles, additional, Conley, Kevin E., additional, Walter, Ludivine, additional, Lovering, Richard M., additional, Chin, Eva R., additional, Jasmin, Bernard J., additional, Marcinek, David J., additional, Menzies, Keir J., additional, and Auwerx, Johan, additional
- Published
- 2016
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- View/download PDF
11. SERCA1 overexpression minimizes skeletal muscle damage in dystrophic mouse models
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Mázala, Davi A. G., primary, Pratt, Stephen J. P., additional, Chen, Dapeng, additional, Molkentin, Jeffery D., additional, Lovering, Richard M., additional, and Chin, Eva R., additional
- Published
- 2015
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12. The role of proteases in excitation-contraction coupling failure in muscular dystrophy
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Mázala, Davi A. G., primary, Grange, Robert W., additional, and Chin, Eva R., additional
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- 2015
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13. Perturbations in intracellular Ca2+handling in skeletal muscle in the G93A*SOD1 mouse model of amyotrophic lateral sclerosis
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Chin, Eva R., primary, Chen, Dapeng, additional, Bobyk, Kostyantyn D., additional, and Mázala, Davi A. G., additional
- Published
- 2014
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14. NAD+ repletion improves muscle function in muscular dystrophy and counters global PARylation.
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Dongryeol Ryu, Hongbo Zhang, Ropelle, Eduardo R., Sorrentino, Vincenzo, Mázala, Davi A. G., Mouchiroud, Laurent, Marshall, Philip L., Campbell, Matthew D., Ali, Amir Safi, Knowels, Gary M., Bellemin, Stéphanie, Iyer, Shama R., Xu Wang, Gariani, Karim, Sauve, Anthony A., Cantó, Carles, Conley, Kevin E., Walter, Ludivine, Lovering, Richard M., and Chin, Eva R.
- Subjects
DUCHENNE muscular dystrophy ,NAD (Coenzyme) ,NEUROMUSCULAR diseases ,LABORATORY rats ,STEM cells ,MESSENGER RNA - Abstract
The article discusses a study which found that nicotinamide adenine dinucleotide (NAD
+ ) repletion is effective in improving muscle function in neuromuscular diseases like Duchene's muscular dystrophy (DMD) and delay both age-related and mdx muscle stem cell senescence. In the mice study, the correlations between the abundance of messenger ribonucleic acid (mRNA) transcripts related to mitochondrial biogenesis, the dystrophin-sarcoglycan complex, and NAD+ were observed.- Published
- 2016
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15. Perturbations in intracellular Ca2+ handling in skeletal muscle in the G93A*SOD1 mouse model of amyotrophic lateral sclerosis.
- Author
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Chin, Eva R., Dapeng Chen, Bobyk, Kostyantyn D., and Mázala, Davi A. G.
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AMYOTROPHIC lateral sclerosis ,CALCIUM channels ,SUPEROXIDE dismutase ,SKELETAL muscle physiology ,LABORATORY mice ,GUANINE ,ADENINE - Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by skeletal muscle atrophy and weakness, ultimately leading to respiratory failure. The purpose of this study was to assess changes in skeletal muscle excitation-contraction (E-C) coupling and intracellular Ca
2+ handling during disease progression in the G93A*SOD1 ALS transgenic (ALS Tg) mouse model. To assess E-C coupling, single muscle fibers were electrically stimulated (10-150 Hz), and intracellular free Ca2+ concentration was assessed using fura-2. There were no differences in peak fura-2 ratio at any stimulation frequency at 70 days (early presymptomatic). However, at 90 days (late presymptomatic) and 120-140 days (symptomatic), fura-2 ratio was increased at 10 Hz in ALS Tg compared with wild-type (WT) fibers (0.670 ± 0.02 vs. 0.585 ± 0.02 for 120-140 days; P < 0.05). There was also a significant increase in resting fura-2 ratio at 90 days (0.351 ± 0.008 vs. 0.390 ± 0.009 in WT vs. ALS Tg; P < 0.05) and 120-140 days (0.374 ± 0.001 vs. 0.415 ± 0.003 in WT vs. ALS Tg; P < 0.05). These increases in intracellular Ca2+ in ALS Tg muscle were associated with reductions in the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase proteins SERCA1 (to 54% and 19% of WT) and SERCA2 (to 56% and 11% of WT) and parvalbumin (to 80 and 62% of WT) in gastrocnemius muscle at 90 and 120-140 days, respectively. There was no change in dihydropyridine receptor/L-type Ca2+ channel at any age. Overall, these data demonstrate minimal changes in electrically evoked Ca2+ transients but elevations in intracellular Ca2+ attributable to decreased Ca2+ -clearance proteins. These data suggest that elevations in cellular Ca2+ could contribute to muscle weakness during disease progression in ALS mice. [ABSTRACT FROM AUTHOR]- Published
- 2014
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16. NAD+repletion improves muscle function in muscular dystrophy and counters global PARylation
- Author
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Ryu, Dongryeol, Zhang, Hongbo, Ropelle, Eduardo R., Sorrentino, Vincenzo, Mázala, Davi A. G., Mouchiroud, Laurent, Marshall, Philip L., Campbell, Matthew D., Ali, Amir Safi, Knowels, Gary M., Bellemin, Stéphanie, Iyer, Shama R., Wang, Xu, Gariani, Karim, Sauve, Anthony A., Cantó, Carles, Conley, Kevin E., Walter, Ludivine, Lovering, Richard M., Chin, Eva R., Jasmin, Bernard J., Marcinek, David J., Menzies, Keir J., and Auwerx, Johan
- Abstract
NAD+treatment can reverse the functional decline in degenerating muscles.
- Published
- 2016
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17. Failure to Resolve Inflammation Contributes to Juvenile-Onset Cardiomyopathy in a Mouse Model of Duchenne Muscular Dystrophy.
- Author
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Novak JS, Lischin A, Uapinyoying P, Hindupur R, Jae Moon Y, Bhattacharya S, Tiufekchiev S, Barone V, Mázala DAG, Gamu IH, Walters G, Panchapakesan K, and Jaiswal JK
- Abstract
The absence of dystrophin protein causes cardiac dysfunction in boys with Duchenne Muscular Dystrophy (DMD). However, the common mouse model of DMD (B10- mdx ) does not manifest cardiac deficits until late adulthood limiting our understanding of the mechanism and therapeutic approaches to target the pediatric-onset cardiac pathology in DMD. We show the mdx mouse model on the DBA/2J genetic background (D2- mdx ) displays juvenile-onset cardiomyopathy. Molecular and histological analysis revealed heightened leukocyte chemotactic signaling and failure to resolve inflammation, leading to chronic inflammation and extracellular matrix (ECM) fibrosis, causing cardiac pathology in juvenile D2- mdx mice. We show that pharmacologically activating the N-formyl peptide receptor 2 (FPR2) - a receptor that physiologically resolves acute inflammation, mitigated chronic cardiac inflammation and fibrosis, and prevented juvenile onset cardiomyopathy in the D2-mdx mice. These studies offer insights into pediatric onset of cardiac damage in DMD, a new therapeutic target, and identify a drug-based potential therapy., Competing Interests: Competing interests. The authors have no competing or financial interests to declare.
- Published
- 2024
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18. SERCA1 Overexpression in Skeletal Muscle Attenuates Muscle Atrophy and Improves Motor Function in a Mouse Model of ALS.
- Author
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Mázala DAG, Chen D, and Chin ER
- Subjects
- Mice, Animals, Endoplasmic Reticulum Chaperone BiP, Calcium metabolism, Fura-2 metabolism, Muscle, Skeletal, Mice, Transgenic, Muscular Atrophy metabolism, Calcium-Transporting ATPases metabolism, Amyotrophic Lateral Sclerosis
- Abstract
Background: Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of muscle mass and muscle function. Previous work from our lab demonstrated that skeletal muscles from a mouse model of ALS show elevated intracellular calcium (Ca2+) levels and heightened endoplasmic reticulum (ER) stress., Objective: To investigate whether overexpression of sarcoplasmic reticulum (SR) Ca2+ ATPase 1 (SERCA1) in skeletal muscle would improve intracellular Ca2+ handling, attenuate ER stress, and improve motor function ALS transgenic mice., Methods: B6SJL-Tg (SOD1*G93A)1Gur/J (ALS-Tg) mice were bred with skeletal muscle α-actinin SERCA1 overexpressing mice to generate wild type (WT), SERCA1 overexpression (WT/+SERCA1), ALS-Tg, and SERCA1 overexpressing ALS-Tg (ALS-Tg/+SERCA1) mice. Motor function (grip test) was assessed weekly and skeletal muscles were harvested at 16 weeks of age to evaluate muscle mass, SR-Ca2+ ATPase activity, levels of SERCA1 and ER stress proteins - protein disulfide isomerase (PDI), Grp78/BiP, and C/EBP homologous protein (CHOP). Single muscle fibers were also isolated from the flexor digitorum brevis muscle to assess changes in resting and peak Fura-2 ratios., Results: ALS-Tg/+SERCA1 mice showed improved motor function, delayed onset of disease, and improved muscle mass compared to ALS-Tg. Further, ALS-Tg/+SERCA1 mice returned levels of SERCA1 protein and SR-Ca2+ ATPase activity back to levels in WT mice. Unexpectedly, SERCA-1 overexpression increased levels of the ER stress maker Grp78/BiP in both WT and ALS-Tg mice, while not altering protein levels of PDI or CHOP. Lastly, single muscle fibers from ALS-Tg/+SERCA1 had similar resting but lower peak Fura-2 levels (at 30 Hz and 100 Hz) compared to ALS-Tg mice., Conclusions: These data indicate that SERCA1 overexpression attenuates the progressive loss of muscle mass and maintains motor function in ALS-Tg mice while not lowering resting Ca2+ levels or ER stress.
- Published
- 2024
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19. Single-cell transcriptomic analysis of the identity and function of fibro/adipogenic progenitors in healthy and dystrophic muscle.
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Uapinyoying P, Hogarth M, Battacharya S, Mázala DAG, Panchapakesan K, Bönnemann CG, and Jaiswal JK
- Abstract
Fibro/adipogenic progenitors (FAPs) are skeletal muscle stromal cells that support regeneration of injured myofibers and their maintenance in healthy muscles. FAPs are related to mesenchymal stem cells (MSCs/MeSCs) found in other adult tissues, but there is poor understanding of the extent of similarity between these cells. Using single-cell RNA sequencing (scRNA-seq) datasets from multiple mouse tissues, we have performed comparative transcriptomic analysis. This identified remarkable transcriptional similarity between FAPs and MeSCs, confirmed the suitability of PDGFRα as a reporter for FAPs, and identified extracellular proteolysis as a new FAP function. Using PDGFRα as a cell surface marker, we isolated FAPs from healthy and dysferlinopathic mouse muscles and performed scRNA-seq analysis. This revealed decreased FAP-mediated Wnt signaling as a potential driver of FAP dysfunction in dysferlinopathic muscles. Analysis of FAPs in dysferlin- and dystrophin-deficient muscles identified a relationship between the nature of muscle pathology and alteration in FAP gene expression., Competing Interests: No conflicts of interests to declare., (© 2023 The Authors.)
- Published
- 2023
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20. Altered muscle niche contributes to myogenic deficit in the D2- mdx model of severe DMD.
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Mázala DAG, Hindupur R, Moon YJ, Shaikh F, Gamu IH, Alladi D, Panci G, Weiss-Gayet M, Chazaud B, Partridge TA, Novak JS, and Jaiswal JK
- Abstract
Lack of dystrophin is the genetic basis for the Duchenne muscular dystrophy (DMD). However, disease severity varies between patients, based on specific genetic modifiers. D2- mdx is a model for severe DMD that exhibits exacerbated muscle degeneration and failure to regenerate even in the juvenile stage of the disease. We show that poor regeneration of juvenile D2- mdx muscles is associated with enhanced inflammatory response to muscle damage that fails to resolve efficiently and supports excessive accumulation of fibroadipogenic progenitors (FAPs). Unexpectedly, the extent of damage and degeneration of juvenile D2- mdx muscle is reduced in adults and is associated with the restoration of the inflammatory and FAP responses to muscle injury. These improvements enhance myogenesis in the adult D2- mdx muscle, reaching levels comparable to the milder (B10- mdx ) mouse model of DMD. Ex vivo co-culture of healthy satellite cells (SCs) with the juvenile D2- mdx FAPs reduced their fusion efficacy and in vivo glucocorticoid treatment of juvenile D2 mouse improved muscle regeneration. Our findings indicate that aberrant stromal cell response contributes to poor myogenesis and greater muscle degeneration in dystrophic juvenile D2- mdx muscles and reversal of this reduces pathology in adult D2- mdx mouse muscle, identifying these as therapeutic targets to treat dystrophic DMD muscles.
- Published
- 2023
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21. Pathogenic role and therapeutic potential of fibro-adipogenic progenitors in muscle disease.
- Author
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Hogarth MW, Uapinyoying P, Mázala DAG, and Jaiswal JK
- Subjects
- Adult, Cell Differentiation, Humans, Muscle Development, Muscle, Skeletal, Adipogenesis, Mesenchymal Stem Cells
- Abstract
Aside from myofibers, numerous mononucleated cells reside in the skeletal muscle. These include the mesenchymal cells called fibro-adipogenic progenitors (FAPs), that support muscle development and regeneration in adult muscles. Recent evidence shows that defects in FAP function contributes to chronic muscle diseases and targeting FAPs offers avenues for treating these diseases., Competing Interests: Declaration of interests No interests to declare., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2022
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22. Endoplasmic reticulum maintains ion homeostasis required for plasma membrane repair.
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Chandra G, Sreetama SC, Mázala DAG, Charton K, VanderMeulen JH, Richard I, and Jaiswal JK
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- Animals, Anoctamins metabolism, Calcium metabolism, Cell Line, Cell Membrane metabolism, Cytosol metabolism, Cytosol physiology, Endoplasmic Reticulum metabolism, Female, Humans, Ions metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Muscular Dystrophies, Limb-Girdle metabolism, Cell Membrane physiology, Endoplasmic Reticulum physiology, Homeostasis physiology
- Abstract
Of the many crucial functions of the ER, homeostasis of physiological calcium increase is critical for signaling. Plasma membrane (PM) injury causes a pathological calcium influx. Here, we show that the ER helps clear this surge in cytoplasmic calcium through an ER-resident calcium pump, SERCA, and a calcium-activated ion channel, Anoctamin 5 (ANO5). SERCA imports calcium into the ER, and ANO5 supports this by maintaining electroneutrality of the ER lumen through anion import. Preventing either of these transporter activities causes cytosolic calcium overload and disrupts PM repair (PMR). ANO5 deficit in limb girdle muscular dystrophy 2L (LGMD2L) patient cells compromises their cytosolic and ER calcium homeostasis. By generating a mouse model of LGMD2L, we find that PM injury causes cytosolic calcium overload and compromises the ability of ANO5-deficient myofibers to repair. Addressing calcium overload in ANO5-deficient myofibers enables them to repair, supporting the requirement of the ER in calcium homeostasis in injured cells and facilitating PMR., (© 2021 Chandra et al.)
- Published
- 2021
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23. Interrogation of Dystrophin and Dystroglycan Complex Protein Turnover After Exon Skipping Therapy.
- Author
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Novak JS, Spathis R, Dang UJ, Fiorillo AA, Hindupur R, Tully CB, Mázala DAG, Canessa E, Brown KJ, Partridge TA, Hathout Y, and Nagaraju K
- Subjects
- Animals, Exons, Mice, Mice, Inbred mdx, Muscle Fibers, Skeletal metabolism, Dystroglycans metabolism, Dystrophin metabolism, Genetic Therapy methods, Muscular Dystrophy, Duchenne therapy, Oligonucleotides, Antisense therapeutic use
- Abstract
Recently, the Food and Drug Administration granted accelerated approvals for four exon skipping therapies -Eteplirsen, Golodirsen, Viltolarsen, and Casimersen -for Duchenne Muscular Dystrophy (DMD). However, these treatments have only demonstrated variable and largely sub-therapeutic levels of restored dystrophin protein in DMD patients, limiting their clinical impact. To better understand variable protein expression and the behavior of truncated dystrophin protein in vivo, we assessed turnover dynamics of restored dystrophin and dystrophin glycoprotein complex (DGC) proteins in mdx mice after exon skipping therapy, compared to those dynamics in wild type mice, using a targeted, highly-reproducible and sensitive, in vivo stable isotope labeling mass spectrometry approach in multiple muscle tissues. Through statistical modeling, we found that restored dystrophin protein exhibited altered stability and slower turnover in treated mdx muscle compared with that in wild type muscle (∼44 d vs. ∼24 d, respectively). Assessment of mRNA transcript stability (quantitative real-time PCR, droplet digital PCR) and dystrophin protein expression (capillary gel electrophoresis, immunofluorescence) support our dystrophin protein turnover measurements and modeling. Further, we assessed pathology-induced muscle fiber turnover through bromodeoxyuridine (BrdU) labeling to model dystrophin and DGC protein turnover in the context of persistent fiber degeneration. Our findings reveal sequestration of restored dystrophin protein after exon skipping therapy in mdx muscle leading to a significant extension of its half-life compared to the dynamics of full-length dystrophin in normal muscle. In contrast, DGC proteins show constant turnover attributable to myofiber degeneration and dysregulation of the extracellular matrix (ECM) in dystrophic muscle. Based on our results, we demonstrate the use of targeted mass spectrometry to evaluate the suitability and functionality of restored dystrophin isoforms in the context of disease and propose its use to optimize alternative gene correction strategies in development for DMD.
- Published
- 2021
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24. NAD+ repletion improves muscle function in muscular dystrophy and counters global PARylation.
- Author
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Ryu D, Zhang H, Ropelle ER, Sorrentino V, Mázala DA, Mouchiroud L, Marshall PL, Campbell MD, Ali AS, Knowels GM, Bellemin S, Iyer SR, Wang X, Gariani K, Sauve AA, Cantó C, Conley KE, Walter L, Lovering RM, Chin ER, Jasmin BJ, Marcinek DJ, Menzies KJ, and Auwerx J
- Subjects
- Adenosine Diphosphate chemistry, Animals, Caenorhabditis elegans, Cell Line, Cytokines chemistry, Fibrosis pathology, Gene Expression Profiling, Inflammation, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Muscular Diseases pathology, Nicotinamide Phosphoribosyltransferase chemistry, Nitrosamines chemistry, RNA, Messenger metabolism, Tyramine analogs & derivatives, Tyramine chemistry, Muscle, Skeletal physiopathology, Muscular Dystrophies pathology, NAD chemistry, Poly ADP Ribosylation
- Abstract
Neuromuscular diseases are often caused by inherited mutations that lead to progressive skeletal muscle weakness and degeneration. In diverse populations of normal healthy mice, we observed correlations between the abundance of mRNA transcripts related to mitochondrial biogenesis, the dystrophin-sarcoglycan complex, and nicotinamide adenine dinucleotide (NAD
+ ) synthesis, consistent with a potential role for the essential cofactor NAD+ in protecting muscle from metabolic and structural degeneration. Furthermore, the skeletal muscle transcriptomes of patients with Duchene's muscular dystrophy (DMD) and other muscle diseases were enriched for various poly[adenosine 5'-diphosphate (ADP)-ribose] polymerases (PARPs) and for nicotinamide N-methyltransferase (NNMT), enzymes that are major consumers of NAD+ and are involved in pleiotropic events, including inflammation. In the mdx mouse model of DMD, we observed significant reductions in muscle NAD+ levels, concurrent increases in PARP activity, and reduced expression of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD+ biosynthesis. Replenishing NAD+ stores with dietary nicotinamide riboside supplementation improved muscle function and heart pathology in mdx and mdx/Utr-/- mice and reversed pathology in Caenorhabditis elegans models of DMD. The effects of NAD+ repletion in mdx mice relied on the improvement in mitochondrial function and structural protein expression (α-dystrobrevin and δ-sarcoglycan) and on the reductions in general poly(ADP)-ribosylation, inflammation, and fibrosis. In combination, these studies suggest that the replenishment of NAD+ may benefit patients with muscular dystrophies or other neuromuscular degenerative conditions characterized by the PARP/NNMT gene expression signatures., (Copyright © 2016, American Association for the Advancement of Science.)- Published
- 2016
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25. SERCA1 overexpression minimizes skeletal muscle damage in dystrophic mouse models.
- Author
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Mázala DA, Pratt SJP, Chen D, Molkentin JD, Lovering RM, and Chin ER
- Subjects
- Animals, Biomarkers blood, Biomechanical Phenomena, Calcium Signaling, Creatine Kinase, MM Form blood, Disease Models, Animal, Genotype, Hypertrophy, Mice, Inbred mdx, Mice, Transgenic, Muscular Dystrophy, Duchenne blood, Muscular Dystrophy, Duchenne genetics, Muscular Dystrophy, Duchenne pathology, Muscular Dystrophy, Duchenne physiopathology, Necrosis, Organ Size, Phenotype, Quadriceps Muscle pathology, Quadriceps Muscle physiopathology, Sarcoplasmic Reticulum Calcium-Transporting ATPases genetics, Severity of Illness Index, Torque, Up-Regulation, Utrophin deficiency, Utrophin genetics, Muscle Contraction, Muscle Strength, Muscular Dystrophy, Duchenne enzymology, Quadriceps Muscle enzymology, Sarcoplasmic Reticulum Calcium-Transporting ATPases metabolism
- Abstract
Duchenne muscular dystrophy (DMD) is characterized by progressive muscle wasting secondary to repeated muscle damage and inadequate repair. Elevations in intracellular free Ca²⁺ have been implicated in disease progression, and sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase 1 (SERCA1) overexpression has been shown to ameliorate the dystrophic phenotype in mdx mice. The purpose of this study was to assess the effects of SERCA1 overexpression in the more severe mdx/Utr(-/-) mouse model of DMD. Mice overexpressing SERCA1 were crossed with mdx/Utr ± mice to generate mdx/Utr(-/-)/+SERCA1 mice and compared with wild-type (WT), WT/+SERCA1, mdx/+SERCA1, and genotype controls. Mice were assessed at ∼12 wk of age for changes in Ca²⁺ handling, muscle mass, quadriceps torque, markers of muscle damage, and response to repeated eccentric contractions. SERCA1-overexpressing mice had a two- to threefold increase in maximal sarcoplasmic reticulum Ca²⁺-ATPase activity compared with WT which was associated with normalization in body mass for both mdx/+SERCA1 and mdx/Utr(-/-)/+SERCA1. Torque deficit in the quadriceps after eccentric injury was 2.7-fold greater in mdx/Utr(-/-) vs. WT mice, but only 1.5-fold greater in mdx/Utr(-/-)/+SERCA1 vs. WT mice, an attenuation of 44%. Markers of muscle damage (% centrally nucleated fibers, necrotic area, and serum creatine kinase levels) were higher in both mdx and mdx/Utr(-/-) vs. WT, and all were attenuated by overexpression of SERCA1. These data indicate that SERCA1 overexpression ameliorates functional impairments and cellular markers of damage in a more severe mouse model of DMD. These findings support targeting intracellular Ca²⁺ control as a therapeutic approach for DMD., (Copyright © 2015 the American Physiological Society.)
- Published
- 2015
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26. The role of proteases in excitation-contraction coupling failure in muscular dystrophy.
- Author
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Mázala DA, Grange RW, and Chin ER
- Subjects
- Animals, Disease Models, Animal, Electric Stimulation, Mice, Inbred mdx, Mice, Knockout, Muscle Fibers, Skeletal drug effects, Muscle Strength, Muscle Weakness, Muscle, Skeletal drug effects, Muscle, Skeletal physiopathology, Muscular Dystrophy, Duchenne drug therapy, Muscular Dystrophy, Duchenne genetics, Muscular Dystrophy, Duchenne physiopathology, Protease Inhibitors pharmacology, Time Factors, Utrophin deficiency, Utrophin genetics, Calcium metabolism, Excitation Contraction Coupling drug effects, Muscle Fibers, Skeletal enzymology, Muscle, Skeletal enzymology, Muscular Dystrophy, Duchenne enzymology, Peptide Hydrolases metabolism
- Abstract
Duchenne muscular dystrophy (DMD) is one of the most frequent types of muscular dystrophy. Alterations in intracellular calcium (Ca(2+)) handling are thought to contribute to the disease severity in DMD, possibly due to the activation of Ca(2+)-activated proteases. The purpose of this study was twofold: 1) to determine whether prolonged excitation-contraction (E-C) coupling disruption following repeated contractions is greater in animals lacking both dystrophin and utrophin (mdx/Utr(-/-)) compared with mice lacking only dystrophin (mdx); and 2) to assess whether protease inhibition can prevent E-C coupling failure following repeated tetani in these dystrophic mouse models. Excitation-contraction coupling was assessed using Fura-2 ratio, as an index of intracellular free Ca(2+) concentration, in response to electrical stimulation of single muscle fibers from the flexor digitorum brevis muscle. Resting Fura-2 ratio was higher in dystrophic compared with control (Con) fibers, but peak Fura-2 ratios during stimulation were similar in dystrophic and Con fibers. One hour after a series of repeated tetani, peak Fura-2 ratios were reduced by 30 ± 5.6%, 23 ± 2%, and 36 ± 3.1% in mdx, mdx/Utr(+/-), and mdx/Utr(-/-), respectively, with the greatest reduction in mdx/Utr(-/-) fibers (P < 0.05). Protease inhibition attenuated this decrease in peak Fura-2 ratio. These data indicate that E-C coupling impairment after repeated contractions is greatest in fibers lacking both dystrophin and utrophin and that prevention of protease activation can mitigate the prolonged E-C coupling impairment. These data further suggest that acute protease inhibition may be useful in reducing muscle weakness in DMD., (Copyright © 2015 the American Physiological Society.)
- Published
- 2015
- Full Text
- View/download PDF
27. Perturbations in intracellular Ca2+ handling in skeletal muscle in the G93A*SOD1 mouse model of amyotrophic lateral sclerosis.
- Author
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Chin ER, Chen D, Bobyk KD, and Mázala DA
- Subjects
- Aging, Animals, Female, Gene Expression Regulation, Enzymologic, Male, Mice, Mice, Transgenic, Muscle Strength genetics, Muscle Strength physiology, Superoxide Dismutase genetics, Amyotrophic Lateral Sclerosis metabolism, Calcium metabolism, Muscle, Skeletal metabolism, Superoxide Dismutase metabolism
- Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by skeletal muscle atrophy and weakness, ultimately leading to respiratory failure. The purpose of this study was to assess changes in skeletal muscle excitation-contraction (E-C) coupling and intracellular Ca(2+) handling during disease progression in the G93A*SOD1 ALS transgenic (ALS Tg) mouse model. To assess E-C coupling, single muscle fibers were electrically stimulated (10-150 Hz), and intracellular free Ca(2+) concentration was assessed using fura-2. There were no differences in peak fura-2 ratio at any stimulation frequency at 70 days (early presymptomatic). However, at 90 days (late presymptomatic) and 120-140 days (symptomatic), fura-2 ratio was increased at 10 Hz in ALS Tg compared with wild-type (WT) fibers (0.670 ± 0.02 vs. 0.585 ± 0.02 for 120-140 days; P < 0.05). There was also a significant increase in resting fura-2 ratio at 90 days (0.351 ± 0.008 vs. 0.390 ± 0.009 in WT vs. ALS Tg; P < 0.05) and 120-140 days (0.374 ± 0.001 vs. 0.415 ± 0.003 in WT vs. ALS Tg; P < 0.05). These increases in intracellular Ca(2+) in ALS Tg muscle were associated with reductions in the sarcoplasmic/endoplasmic reticulum Ca(2+) ATPase proteins SERCA1 (to 54% and 19% of WT) and SERCA2 (to 56% and 11% of WT) and parvalbumin (to 80 and 62% of WT) in gastrocnemius muscle at 90 and 120-140 days, respectively. There was no change in dihydropyridine receptor/l-type Ca(2+) channel at any age. Overall, these data demonstrate minimal changes in electrically evoked Ca(2+) transients but elevations in intracellular Ca(2+) attributable to decreased Ca(2+)-clearance proteins. These data suggest that elevations in cellular Ca(2+) could contribute to muscle weakness during disease progression in ALS mice., (Copyright © 2014 the American Physiological Society.)
- Published
- 2014
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