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Duchenne Muscular Dystrophy: Mechanisms and Therapeutic Strategies
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Duchenne Muscular Dystrophy: Mechanisms and Therapeutic Strategies

A special issue of Life (ISSN 2075-1729). This special issue belongs to the section "Cell Biology and Tissue Engineering".

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 40461

Special Issue Editor

Dr. Gopal J. Babu

E-Mail Website
Guest Editor
Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers University, New Brunswick, NJ 07103, USA
Interests: SR calcium handling in heart and skeletal muscles; muscle differentiation; mitochondrial calcium; Duchenne muscular dystrophy; myocardial infarction; heart failure; AAV mediated gene therapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Duchenne muscular dystrophy (DMD) is one of the most prevalent forms of muscular dystrophy. DMD is an X-linked recessive disorder, epidemiologically reported to affect 1 in 3600–6000 male live births. DMD is caused by mutations in the dystrophin gene resulting in a loss of functional dystrophin protein in skeletal and cardiac muscles. This leads to the degeneration of muscle fibers, necrosis, inflammation, fibrosis, and fatty replacement resulting in muscle weakness, respiratory and cardiac failure, and premature death. Despite these findings and several clinical trials, there is no curative treatment for this disease. Although the loss of dystrophin is the primary cause, several cellular and molecular factors including calcium handling proteins, myogenic factors, proteases, signaling molecules, and altered expressions of genes have been identified as key players in muscle pathogenesis and the development of dystrophic cardiomyopathy. This Special Issue will provide a general overview of cellular and molecular mechanisms associated with muscle wasting and the development of dystrophic cardiomyopathy and therapeutic strategies in treating DMD.

We look forward to your contributions of original research or review articles that fit the theme of this Special Issue.

Dr. Gopal J. Babu
Guest Editor

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Keywords

  • Duchenne muscular dystrophy
  • dystrophin
  • Calcium
  • gene therapy
  • muscle wasting
  • cardiomyopathy
  • muscle regeneration
  • metabolic dysfunction
  • proteases
  • inflammation

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Published Papers (10 papers)

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Research

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16 pages, 4809 KiB  
Article
Hematopoietic Prostaglandin D Synthase Inhibitor PK007 Decreases Muscle Necrosis in DMD mdx Model Mice
by Sai Yarlagadda, Christina Kulis, Peter G. Noakes and Mark L. Smythe
Life 2021, 11(9), 994; https://doi.org/10.3390/life11090994 - 21 Sep 2021
Cited by 5 | Viewed by 3594
Abstract
Duchenne muscular dystrophy (DMD) is characterized by progressive muscle weakness and wasting due to the lack of dystrophin protein. The acute phase of DMD is characterized by muscle necrosis and increased levels of the pro-inflammatory mediator, prostaglandin D2 (PGD2). Inhibiting the production of [...] Read more.
Duchenne muscular dystrophy (DMD) is characterized by progressive muscle weakness and wasting due to the lack of dystrophin protein. The acute phase of DMD is characterized by muscle necrosis and increased levels of the pro-inflammatory mediator, prostaglandin D2 (PGD2). Inhibiting the production of PGD2 by inhibiting hematopoietic prostaglandin D synthase (HPGDS) may alleviate inflammation and decrease muscle necrosis. We tested our novel HPGDS inhibitor, PK007, in the mdx mouse model of DMD. Our results show that hindlimb grip strength was two-fold greater in the PK007-treated mdx group, compared to untreated mdx mice, and displayed similar muscle strength to strain control mice (C57BL/10ScSn). Histological analyses showed a decreased percentage of regenerating muscle fibers (~20% less) in tibialis anterior (TA) and gastrocnemius muscles and reduced fibrosis in the TA muscle in PK007-treated mice. Lastly, we confirmed that the DMD blood biomarker, muscle creatine kinase activity, was also reduced by ~50% in PK007-treated mdx mice. We conclude that our HPGDS inhibitor, PK007, has effectively reduced muscle inflammation and fibrosis in a DMD mdx mouse model. Full article
(This article belongs to the Special Issue Duchenne Muscular Dystrophy: Mechanisms and Therapeutic Strategies)
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16 pages, 2903 KiB  
Article
Dystrophin Dp71 Subisoforms Localize to the Mitochondria of Human Cells
by Emma Tabe Eko Niba, Hiroyuki Awano, Tomoko Lee, Yasuhiro Takeshima, Masakazu Shinohara, Hisahide Nishio and Masafumi Matsuo
Life 2021, 11(9), 978; https://doi.org/10.3390/life11090978 - 16 Sep 2021
Cited by 3 | Viewed by 3176
Abstract
Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease caused by deficiency in dystrophin, a protein product encoded by the DMD gene. Mitochondrial dysfunction is now attracting much attention as a central player in DMD pathology. However, dystrophin has never been explored [...] Read more.
Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease caused by deficiency in dystrophin, a protein product encoded by the DMD gene. Mitochondrial dysfunction is now attracting much attention as a central player in DMD pathology. However, dystrophin has never been explored in human mitochondria. Here, we analyzed dystrophin in cDNAs and mitochondrial fractions of human cells. Mitochondrial fraction was obtained using a magnetic-associated cell sorting (MACS) technology. Dystrophin was analyzed by reverse transcription (RT)-PCR and western blotting using an antibody against the dystrophin C-terminal. In isolated mitochondrial fraction from HEK293 cells, dystrophin was revealed as a band corresponding to Dp71b and Dp71ab subisoforms. Additionally, in mitochondria from HeLa, SH-SY5Y, CCL-136 and HepG2 cells, signals for Dp71b and Dp71ab were revealed as well. Concomitantly, dystrophin mRNAs encoding Dp71b and Dp71ab were disclosed by RT-PCR in these cells. Primary cultured myocytes from three dystrophinopathy patients showed various levels of mitochondrial Dp71 expression. Coherently, levels of mRNA were different in all cells reflecting the protein content, which indicated predominant accumulation of Dp71. Dystrophin was demonstrated to be localized to human mitochondrial fraction, specifically as Dp71 subisoforms. Myocytes derived from dystrophinopathy patients manifested different levels of mitochondrial Dp71, with higher expression revealed in myocytes from Becker muscular dystrophy (BMD) patient-derived myocytes. Full article
(This article belongs to the Special Issue Duchenne Muscular Dystrophy: Mechanisms and Therapeutic Strategies)
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13 pages, 3508 KiB  
Article
Validation of Chemokine Biomarkers in Duchenne Muscular Dystrophy
by Michael Ogundele, Jesslyn S. Zhang, Mansi V. Goswami, Marissa L. Barbieri, Utkarsh J. Dang, James S. Novak, Eric P. Hoffman, Kanneboyina Nagaraju, CINRG-DNHS Investigators and Yetrib Hathout
Life 2021, 11(8), 827; https://doi.org/10.3390/life11080827 - 13 Aug 2021
Cited by 10 | Viewed by 4034
Abstract
Duchenne muscular dystrophy (DMD) is a progressive muscle disease involving complex skeletal muscle pathogenesis. The pathogenesis is triggered by sarcolemma instability due to the lack of dystrophin protein expression, leading to Ca2+ influx, muscle fiber apoptosis, inflammation, muscle necrosis, and fibrosis. Our [...] Read more.
Duchenne muscular dystrophy (DMD) is a progressive muscle disease involving complex skeletal muscle pathogenesis. The pathogenesis is triggered by sarcolemma instability due to the lack of dystrophin protein expression, leading to Ca2+ influx, muscle fiber apoptosis, inflammation, muscle necrosis, and fibrosis. Our lab recently used two high-throughput multiplexing techniques (e.g., SomaScan® aptamer assay and tandem mass tag-(TMT) approach) and identified a series of serum protein biomarkers tied to different pathobiochemical pathways. In this study, we focused on validating the circulating levels of three proinflammatory chemokines (CCL2, CXCL10, and CCL18) that are believed to be involved in an early stage of muscle pathogenesis. We used highly specific and reproducible MSD ELISA assays and examined the association of these chemokines with DMD pathogenesis, age, disease severity, and response to glucocorticoid treatment. As expected, we confirmed that these three chemokines were significantly elevated in serum and muscle samples of DMD patients relative to age-matched healthy controls (p-value < 0.05, CCL18 was not significantly altered in muscle samples). These three chemokines were not significantly elevated in Becker muscular dystrophy (BMD) patients, a milder form of dystrophinopathy, when compared in a one-way ANOVA to a control group but remained significantly elevated in the age-matched DMD group (p < 0.05). CCL2 and CCL18 but not CXCL10 declined with age in DMD patients, whereas all three chemokines remained unchanged with age in BMD and controls. Only CCL2 showed significant association with time to climb four steps in the DMD group (r = 0.48, p = 0.038) and neared significant association with patients’ reported outcome in the BMD group (r = 0.39, p = 0.058). Furthermore, CCL2 was found to be elevated in a serum of the mdx mouse model of DMD, relative to wild-type mouse model. This study suggests that CCL2 might be a suitable candidate biomarker for follow-up studies to demonstrate its physiological significance and clinical utility in DMD. Full article
(This article belongs to the Special Issue Duchenne Muscular Dystrophy: Mechanisms and Therapeutic Strategies)
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10 pages, 1602 KiB  
Article
Skeletal Effects of Bone-Targeted TGFbeta Inhibition in a Mouse Model of Duchenne Muscular Dystrophy
by Juliana Marulanda, Iris Boraschi-Diaz, Pierre Beauparlant, Philippe Crine and Frank Rauch
Life 2021, 11(8), 791; https://doi.org/10.3390/life11080791 - 5 Aug 2021
Cited by 1 | Viewed by 2980
Abstract
Duchenne muscular dystrophy (DMD) is a severe progressive muscle disease that is frequently associated with secondary osteoporosis. Previous studies have shown that TGFbeta inactivating antibody improves the muscle phenotype in mdx mice, a model of DMD. In the present study, we assessed the [...] Read more.
Duchenne muscular dystrophy (DMD) is a severe progressive muscle disease that is frequently associated with secondary osteoporosis. Previous studies have shown that TGFbeta inactivating antibody improves the muscle phenotype in mdx mice, a model of DMD. In the present study, we assessed the skeletal effects of treatment with a bone-targeted TGFbeta antibody (PCT-011) in mdx mice. Micro-computed tomography showed that 8 weeks of intraperitoneal administration of PCT-011 (10 mg per kg body mass, 3 times per week) was associated with more than twofold higher trabecular bone volume at the distal femur, which was explained by a higher trabecular number. At the femoral midshaft, PCT-011 exposure increased cortical thickness but did not significantly affect the results of three-point bending tests. Histomorphometric analyses of the lumbar vertebra 4 showed that PCT-011 treatment led to a lower bone formation rate. In conclusion, treatment with the TGFbeta antibody PCT-011 had a positive effect on bone development in mdx mice. Inhibiting TGFbeta activity thus appears to be a promising approach to treat bone fragility in the context of DMD. Full article
(This article belongs to the Special Issue Duchenne Muscular Dystrophy: Mechanisms and Therapeutic Strategies)
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16 pages, 287 KiB  
Article
Prevalence of Bladder and Bowel Dysfunction in Duchenne Muscular Dystrophy Using the Childhood Bladder and Bowel Dysfunction Questionnaire
by Judith M. Lionarons, Imelda J. M. de Groot, Johanna M. Fock, Sylvia Klinkenberg, Desiree M. J. Vrijens, Anita C. E. Vreugdenhil, Evita G. Medici-van den Herik, Inge Cuppen, Bregje Jaeger, Erik H. Niks, Rinske Hoogerhuis, Nicky Platte-van Attekum, Frans J. M. Feron, Catharina G. Faber, Jos G. M. Hendriksen and Johan S. H. Vles
Life 2021, 11(8), 772; https://doi.org/10.3390/life11080772 - 30 Jul 2021
Cited by 12 | Viewed by 3474
Abstract
Introduction: Lower urinary tract symptoms (LUTS) and gastrointestinal (GI) problems are common in Duchenne muscular dystrophy (DMD), but not systematically assessed in regular care. We aimed to determine the prevalence of bladder and bowel dysfunction (BBD) in DMD patients compared with healthy controls [...] Read more.
Introduction: Lower urinary tract symptoms (LUTS) and gastrointestinal (GI) problems are common in Duchenne muscular dystrophy (DMD), but not systematically assessed in regular care. We aimed to determine the prevalence of bladder and bowel dysfunction (BBD) in DMD patients compared with healthy controls (HC). Methods: The Childhood Bladder and Bowel Dysfunction Questionnaire (CBBDQ) based on the International Rome III criteria and the International Children’s Continence Society was filled out by 57 DMD patients and 56 HC. Additionally, possible associations of BBD with, for example, medication use or quality of life were evaluated in an additional questionnaire developed by experts. Results: In 74% of patients versus 56% of HC ≥ 1 LUTS (n.s.) were reported, 68% of patients versus 39% of HC reported ≥1 bowel symptom (p = 0.002) and 53% of patients versus 30% of HC reported combined LUTS and bowel symptoms (p = 0.019). A negative impact of BBD on daily life functioning was reported by 42% of patients. Conclusions: These data underscore that standard screening for BBD is needed and that the CBBDQ could be of added value to optimize DMD care. Full article
(This article belongs to the Special Issue Duchenne Muscular Dystrophy: Mechanisms and Therapeutic Strategies)
18 pages, 1805 KiB  
Article
Influence of Different Types of Corticosteroids on Heart Rate Variability of Individuals with Duchenne Muscular Dystrophy—A Pilot Cross Sectional Study
by Rodrigo Martins Dias, Rosangela Akemi Hoshi, Luiz Carlos Marques Vanderlei, Carlos Bandeira de Mello Monteiro, Mayra Priscila Boscolo Alvarez, Tânia Brusque Crocetta, Luis Fernando Grossklauss, Deborah Cristina Gonçalves Luiz Fernani, Maria Tereza Artero Prado Dantas, Fabiana Paula Almeida Martins, David M. Garner, Luiz Carlos Abreu, Celso Ferreira and Talita Dias da Silva
Life 2021, 11(8), 752; https://doi.org/10.3390/life11080752 - 27 Jul 2021
Cited by 5 | Viewed by 4358
Abstract
Individuals with Duchenne Muscular Dystrophy (DMD) have an impairment of cardiac autonomic function categorized by parasympathetic reduction and sympathetic predominance. The objective of this study was to assess the cardiac autonomic modulation of individuals with DMD undergoing therapy with Prednisone/Prednisolone and Deflazacort and [...] Read more.
Individuals with Duchenne Muscular Dystrophy (DMD) have an impairment of cardiac autonomic function categorized by parasympathetic reduction and sympathetic predominance. The objective of this study was to assess the cardiac autonomic modulation of individuals with DMD undergoing therapy with Prednisone/Prednisolone and Deflazacort and compare with individuals with DMD without the use of these medications and a typically developed control group. Methods: A cross-sectional study was completed, wherein 40 boys were evaluated. The four treatment groups were: Deflazacort; Prednisone/Prednisolone; no corticoid use; and typical development. Heart Rate Variability (HRV) was investigated via linear indices (Time Domain and Frequency Domain) and non-linear indices Results: The results of this study revealed that individuals with DMD undertaking pharmacotherapies with Prednisolone demonstrated HRV comparable to the Control Typically Developed (CTD) group. In contrast, individuals with DMD undergoing pharmacotherapies with Deflazacort achieved lower HRV, akin to individuals with DMD without any medications, as demonstrated in the metrics: RMSSD; LF (n.u.), HF (n.u.), LF/HF; SD1, α1, and α1/α2, and a significant effect for SD1/SD2; %DET and Ratio; Shannon Entropy, 0 V%, 2 LV% and 2 ULV%. Conclusions: Corticosteroids have the potential to affect the cardiac autonomic modulation in adolescents with DMD. The use of Prednisone/Prednisolone appears to promote improved responses in terms of sympathovagal activity as opposed to Deflazacort. Full article
(This article belongs to the Special Issue Duchenne Muscular Dystrophy: Mechanisms and Therapeutic Strategies)
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13 pages, 3288 KiB  
Article
Accelerating the Mdx Heart Histo-Pathology through Physical Exercise
by Jacopo Morroni, Leonardo Schirone, Daniele Vecchio, Carmine Nicoletti, Luca D’Ambrosio, Valentina Valenti, Sebastiano Sciarretta, Biliana Lozanoska-Ochser and Marina Bouchè
Life 2021, 11(7), 706; https://doi.org/10.3390/life11070706 - 17 Jul 2021
Cited by 6 | Viewed by 3178
Abstract
Chronic cardiac muscle inflammation and fibrosis are key features of Duchenne Muscular Dystrophy (DMD). Around 90% of 18-year-old patients already show signs of DMD-related cardiomyopathy, and cardiac failure is rising as the main cause of death among DMD patients. The evaluation of novel [...] Read more.
Chronic cardiac muscle inflammation and fibrosis are key features of Duchenne Muscular Dystrophy (DMD). Around 90% of 18-year-old patients already show signs of DMD-related cardiomyopathy, and cardiac failure is rising as the main cause of death among DMD patients. The evaluation of novel therapies for the treatment of dystrophic heart problems depends on the availability of animal models that closely mirror the human pathology. The widely used DMD animal model, the mdx mouse, presents a milder cardiac pathology compared to humans, with a late onset, which precludes large-scale and reliable studies. In this study, we used an exercise protocol to accelerate and worsen the cardiac pathology in mdx mice. The mice were subjected to a 1 h-long running session on a treadmill, at moderate speed, twice a week for 8 weeks. We demonstrate that subjecting young mdx mice (4-week-old) to “endurance” exercise accelerates heart pathology progression, as shown by early fibrosis deposition, increases necrosis and inflammation, and reduces heart function compared to controls. We believe that our exercised mdx model represents an easily reproducible and useful tool to study the molecular and cellular networks involved in dystrophic heart alterations, as well as to evaluate novel therapeutic strategies aimed at ameliorating dystrophic heart pathology. Full article
(This article belongs to the Special Issue Duchenne Muscular Dystrophy: Mechanisms and Therapeutic Strategies)
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17 pages, 8276 KiB  
Article
Mass Spectrometric Profiling of Extraocular Muscle and Proteomic Adaptations in the mdx-4cv Model of Duchenne Muscular Dystrophy
by Stephen Gargan, Paul Dowling, Margit Zweyer, Jens Reimann, Michael Henry, Paula Meleady, Dieter Swandulla and Kay Ohlendieck
Life 2021, 11(7), 595; https://doi.org/10.3390/life11070595 - 22 Jun 2021
Cited by 15 | Viewed by 3723
Abstract
Extraocular muscles (EOMs) represent a specialized type of contractile tissue with unique cellular, physiological, and biochemical properties. In Duchenne muscular dystrophy, EOMs stay functionally unaffected in the course of disease progression. Therefore, it was of interest to determine their proteomic profile in dystrophinopathy. [...] Read more.
Extraocular muscles (EOMs) represent a specialized type of contractile tissue with unique cellular, physiological, and biochemical properties. In Duchenne muscular dystrophy, EOMs stay functionally unaffected in the course of disease progression. Therefore, it was of interest to determine their proteomic profile in dystrophinopathy. The proteomic survey of wild type mice and the dystrophic mdx-4cv model revealed a broad spectrum of sarcomere-associated proteoforms, including components of the thick filament, thin filament, M-band and Z-disk, as well as a variety of muscle-specific markers. Interestingly, the mass spectrometric analysis revealed unusual expression levels of contractile proteins, especially isoforms of myosin heavy chain. As compared to diaphragm muscle, both proteomics and immunoblotting established isoform MyHC14 as a new potential marker in wild type EOMs, in addition to the previously identified isoforms MyHC13 and MyHC15. Comparative proteomics was employed to establish alterations in the protein expression profile between normal EOMs and dystrophin-lacking EOMs. The analysis of mdx-4cv EOMs identified elevated levels of glycolytic enzymes and molecular chaperones, as well as decreases in mitochondrial enzymes. These findings suggest a process of adaptation in dystrophin-deficient EOMs via a bioenergetic shift to more glycolytic metabolism, as well as an efficient cellular stress response in EOMs in dystrophinopathy. Full article
(This article belongs to the Special Issue Duchenne Muscular Dystrophy: Mechanisms and Therapeutic Strategies)
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Review

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19 pages, 1077 KiB  
Review
Non-Invasive Respiratory Assessment in Duchenne Muscular Dystrophy: From Clinical Research to Outcome Measures
by Francesca Pennati, Antonella LoMauro, Maria Grazia D’Angelo and Andrea Aliverti
Life 2021, 11(9), 947; https://doi.org/10.3390/life11090947 - 10 Sep 2021
Cited by 12 | Viewed by 4602
Abstract
Ventilatory failure, due to the progressive wasting of respiratory muscles, is the main cause of death in patients with Duchenne muscular dystrophy (DMD). Reliable measures of lung function and respiratory muscle action are important to monitor disease progression, to identify early signs of [...] Read more.
Ventilatory failure, due to the progressive wasting of respiratory muscles, is the main cause of death in patients with Duchenne muscular dystrophy (DMD). Reliable measures of lung function and respiratory muscle action are important to monitor disease progression, to identify early signs of ventilatory insufficiency and to plan individual respiratory management. Moreover, the current development of novel gene-modifying and pharmacological therapies highlighted the urgent need of respiratory outcomes to quantify the effects of these therapies. Pulmonary function tests represent the standard of care for lung function evaluation in DMD, but provide a global evaluation of respiratory involvement, which results from the interaction between different respiratory muscles. Currently, research studies have focused on finding novel outcome measures able to describe the behavior of individual respiratory muscles. This review overviews the measures currently identified in clinical research to follow the progressive respiratory decline in patients with DMD, from a global assessment to an individual structure–function muscle characterization. We aim to discuss their strengths and limitations, in relation to their current development and suitability as outcome measures for use in a clinical setting and as in upcoming drug trials in DMD. Full article
(This article belongs to the Special Issue Duchenne Muscular Dystrophy: Mechanisms and Therapeutic Strategies)
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11 pages, 668 KiB  
Review
The Interplay of Mitophagy and Inflammation in Duchenne Muscular Dystrophy
by Andrea L. Reid and Matthew S. Alexander
Life 2021, 11(7), 648; https://doi.org/10.3390/life11070648 - 4 Jul 2021
Cited by 27 | Viewed by 5209
Abstract
Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease caused by a pathogenic disruption of the DYSTROPHIN gene that results in non-functional dystrophin protein. DMD patients experience loss of ambulation, cardiac arrhythmia, metabolic syndrome, and respiratory failure. At the molecular level, the lack [...] Read more.
Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease caused by a pathogenic disruption of the DYSTROPHIN gene that results in non-functional dystrophin protein. DMD patients experience loss of ambulation, cardiac arrhythmia, metabolic syndrome, and respiratory failure. At the molecular level, the lack of dystrophin in the muscle results in myofiber death, fibrotic infiltration, and mitochondrial dysfunction. There is no cure for DMD, although dystrophin-replacement gene therapies and exon-skipping approaches are being pursued in clinical trials. Mitochondrial dysfunction is one of the first cellular changes seen in DMD myofibers, occurring prior to muscle disease onset and progresses with disease severity. This is seen by reduced mitochondrial function, abnormal mitochondrial morphology and impaired mitophagy (degradation of damaged mitochondria). Dysfunctional mitochondria release high levels of reactive oxygen species (ROS), which can activate pro-inflammatory pathways such as IL-1β and IL-6. Impaired mitophagy in DMD results in increased inflammation and further aggravates disease pathology, evidenced by increased muscle damage and increased fibrosis. This review will focus on the critical interplay between mitophagy and inflammation in Duchenne muscular dystrophy as a pathological mechanism, as well as describe both candidate and established therapeutic targets that regulate these pathways. Full article
(This article belongs to the Special Issue Duchenne Muscular Dystrophy: Mechanisms and Therapeutic Strategies)
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