Translating golden retriever muscular dystrophy microarray findings to novel biomarkers for cardiac/skeletal muscle function in Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a severe and progressive muscle wasting disorder, affecting one in 3500 to 5000 boys worldwide. The NO-sGC-cGMP pathway plays an important role in skeletal muscle function, primarily by improving blood flow and oxygen supply to the muscles during exercise. In fact, PDE5 inhibitors have previously been investigated as a potential therapy for DMD, however, a large-scale Phase III clinical trial did not meet its primary endpoint. Since the efficacy of PDE5i is dependent on sufficient endogenous NO production, which might be impaired in DMD, we investigated if NO-independent sGC stimulators, could have therapeutic benefits in a mouse model of DMD. Male mdx/mTRG2 mice aged six weeks were given food supplemented with the sGC stimulator, BAY-747 (150 mg/kg of food) or food alone (untreated) ad libitum for 16 weeks. Untreated C57BL6/J mice were used as wild type (WT) controls. Assessments of the four-limb hang, grip strength, running wheel and serum creatine kinase (CK) levels showed that mdx/mTRG2 mice had significantly reduced skeletal muscle function and severe muscle damage compared to WT mice. Treatment with BAY-747 improved grip strength and running speed, and these mice also had reduced CK levels compared to untreated mdx/mTRG2 mice. We also observed increased inflammation and fibrosis in the skeletal muscle of mdx/mTRG2 mice compared to WT. While gene expression of pro-inflammatory cytokines and some pro-fibrotic markers in the skeletal muscle was reduced following BAY-747 treatment, there was no reduction in infiltration of myeloid immune cells nor collagen deposition. In conclusion, treatment with BAY-747 significantly improves several functional and pathological parameters of the skeletal muscle in mdx/mTRG2 mice. However, the effect size was moderate and therefore, more studies are needed to fully understand the potential treatment benefit of sGC stimulators in DMD.

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Ketogenic diet with medium‐chain triglycerides restores skeletal muscle function and pathology in a rat model of Duchenne muscular dystrophy

The FASEB Journal ◽

10.1096/fj.202100629r ◽

2021 ◽

Vol 35 (9) ◽

Author(s):

Yuri Fujikura ◽

Hidetoshi Sugihara ◽

Masaki Hatakeyama ◽

Katsutaka Oishi ◽

Keitaro Yamanouchi

Keyword(s):

Skeletal Muscle ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Ketogenic Diet ◽

Rat Model ◽

Muscle Function ◽

Medium Chain Triglycerides ◽

Skeletal Muscle Function ◽

Medium Chain

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Increasing taurine intake and taurine synthesis improves skeletal muscle function in the mdx mouse model for Duchenne muscular dystrophy

The Journal of Physiology ◽

10.1113/jp271418 ◽

2016 ◽

Vol 594 (11) ◽

pp. 3095-3110 ◽

Cited By ~ 33

Author(s):

Jessica R. Terrill ◽

Gavin J. Pinniger ◽

Jamie A. Graves ◽

Miranda D. Grounds ◽

Peter G. Arthur

Keyword(s):

Skeletal Muscle ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Mouse Model ◽

Muscle Function ◽

Mdx Mouse ◽

Skeletal Muscle Function

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Galectin‐3 and N ‐acetylglucosamine promote myogenesis and improve skeletal muscle function in the mdx model of Duchenne muscular dystrophy

The FASEB Journal ◽

10.1096/fj.201701151rrr ◽

2018 ◽

Vol 32 (12) ◽

pp. 6445-6455 ◽

Cited By ~ 4

Author(s):

Ann Rancourt ◽

Sébastien S. Dufresne ◽

Guillaume St‐Pierre ◽

Julie‐Christine Lévesque ◽

Haruka Nakamura ◽

...

Keyword(s):

Skeletal Muscle ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Muscle Function ◽

Skeletal Muscle Function ◽

Galectin 3

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Intraosseous transplant of dystrophin expressing chimeric (DEC) cells improves skeletal muscle function in mdx mouse model of Duchenne muscular dystrophy

Advances in Interventional Cardiology ◽

10.5114/aic.2021.110990 ◽

2021 ◽

Author(s):

Mohammad Malik ◽

Maria Siemionow ◽

Joanna Cwykiel ◽

Ahlke Heydemann ◽

Jesus Garcia-Martinez ◽

...

Keyword(s):

Skeletal Muscle ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Mouse Model ◽

Muscle Function ◽

Mdx Mouse ◽

Skeletal Muscle Function

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Neopterin/7,8-dihydroneopterin is elevated in Duchenne muscular dystrophy patients and protects mdx skeletal muscle function

Experimental Physiology ◽

10.1113/ep087031 ◽

2018 ◽

Vol 103 (7) ◽

pp. 995-1009 ◽

Cited By ~ 10

Author(s):

Angus Lindsay ◽

Alexandra Schmiechen ◽

Christopher M. Chamberlain ◽

James M. Ervasti ◽

Dawn A. Lowe

Keyword(s):

Skeletal Muscle ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Muscle Function ◽

Skeletal Muscle Function

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Relevant aspects of golden retriever muscular dystrophy for the study of Duchenne muscular dystrophy in humans

Ciência Rural ◽

10.1590/0103-8478cr20160470 ◽

2017 ◽

Vol 47 (10) ◽

Author(s):

Julieta Rodini Engrácia de Moraes ◽

Lygia Maria Mouri Malvestio ◽

Isabela Mancini Martins ◽

Patrícia Regina Erdmann Mosko ◽

Jair Rodini Engracia Filho ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Phenotypic Expression ◽

Clinical Signs ◽

Golden Retriever ◽

Golden Retriever Muscular Dystrophy ◽

Cardiac Muscles ◽

Representative Model ◽

Progressive Weakness

ABSTRACT: Golden Retriever muscular dystrophy (GRMD) is the most representative model for studying Duchenne muscular dystrophy (DMD) in humans, owing its phenotypic expression. DMD is a recessive disorder linked to the X chromosome in which the loss of dystrophin induces progressive weakness and degeneration of the skeletal and cardiac muscles, which lead to replacement by connective and adipose tissues. Onset of clinical signs occurs between 2 and 5 years of age, and many patients die from heart or respiratory failure. The main studies concerning dystrophic Golden Retrievers (DGR) sought to elucidate the pathophysiology of the disease and its clinical implications to develop therapies and alternative treatments to improve the quality of life and increase longevity of DMD patients. This review presents an overview of relevant contributions of the DGR model for elucidating DMD in humans.

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Co-Transplantation of Bone Marrow-MSCs and Myogenic Stem/Progenitor Cells from Adult Donors Improves Muscle Function of Patients with Duchenne Muscular Dystrophy

Cells ◽

10.3390/cells9051119 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1119

Author(s):

Aleksandra Klimczak ◽

Agnieszka Zimna ◽

Agnieszka Malcher ◽

Urszula Kozlowska ◽

Katarzyna Futoma ◽

...

Keyword(s):

Skeletal Muscle ◽

Bone Marrow ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Progenitor Cells ◽

Muscle Function ◽

Progenitor Cell ◽

Genetic Disorder ◽

Cell Populations ◽

Muscle Fibres

Duchenne muscular dystrophy (DMD) is a genetic disorder associated with a progressive deficiency of dystrophin that leads to skeletal muscle degeneration. In this study, we tested the hypothesis that a co-transplantation of two stem/progenitor cell populations, namely bone marrow-derived mesenchymal stem cells (BM-MSCs) and skeletal muscle-derived stem/progenitor cells (SM-SPCs), directly into the dystrophic muscle can improve the skeletal muscle function of DMD patients. Three patients diagnosed with DMD, confirmed by the dystrophin gene mutation, were enrolled into a study approved by the local Bioethics Committee (no. 79/2015). Stem/progenitor cells collected from bone marrow and skeletal muscles of related healthy donors, based on HLA matched antigens, were expanded in a closed MC3 cell culture system. A simultaneous co-transplantation of BM-MSCs and SM-SPCs was performed directly into the biceps brachii (two patients) and gastrocnemius (one patient). During a six-month follow-up, the patients were examined with electromyography (EMG) and monitored for blood kinase creatine level. Muscle biopsies were examined with histology and assessed for dystrophin at the mRNA and protein level. A panel of 27 cytokines was analysed with multiplex ELISA. We did not observe any adverse effects after the intramuscular administration of cells. The efficacy of BM-MSC and SM-SPC application was confirmed through an EMG assessment by an increase in motor unit parameters, especially in terms of duration, amplitude range, area, and size index. The beneficial effect of cellular therapy was confirmed by a decrease in creatine kinase levels and a normalised profile of pro-inflammatory cytokines. BM-MSCs may support the pro-regenerative potential of SM-SPCs thanks to their trophic, paracrine, and immunomodulatory activity. Both applied cell populations may fuse with degenerating skeletal muscle fibres in situ, facilitating skeletal muscle recovery. However, further studies are required to optimise the dose and timing of stem/progenitor cell delivery.

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DOCK3 is a dosage-sensitive regulator of skeletal muscle and Duchenne muscular dystrophy-associated pathologies

Human Molecular Genetics ◽

10.1093/hmg/ddaa173 ◽

2020 ◽

Vol 29 (17) ◽

pp. 2855-2871

Author(s):

Andrea L Reid ◽

Yimin Wang ◽

Adrienne Samani ◽

Rylie M Hightower ◽

Michael A Lopez ◽

...

Keyword(s):

Skeletal Muscle ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Muscle Function ◽

Myogenic Differentiation ◽

Nucleotide Exchange ◽

Dystrophic Muscle ◽

Guanine Nucleotide Exchange ◽

Myogenic Factors

Abstract DOCK3 is a member of the DOCK family of guanine nucleotide exchange factors that regulate cell migration, fusion and viability. Previously, we identified a dysregulated miR-486/DOCK3 signaling cascade in dystrophin-deficient muscle, which resulted in the overexpression of DOCK3; however, little is known about the role of DOCK3 in muscle. Here, we characterize the functional role of DOCK3 in normal and dystrophic skeletal muscle. Utilizing Dock3 global knockout (Dock3 KO) mice, we found that the haploinsufficiency of Dock3 in Duchenne muscular dystrophy mice improved dystrophic muscle pathologies; however, complete loss of Dock3 worsened muscle function. Adult Dock3 KO mice have impaired muscle function and Dock3 KO myoblasts are defective for myogenic differentiation. Transcriptomic analyses of Dock3 KO muscles reveal a decrease in myogenic factors and pathways involved in muscle differentiation. These studies identify DOCK3 as a novel modulator of muscle health and may yield therapeutic targets for treating dystrophic muscle symptoms.

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