Evidence of Insulin Resistance and Other Metabolic Alterations in Boys with Duchenne or Becker Muscular Dystrophy

BackgroundDuchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, which codes for the dystrophin protein. While progress has been made in defining the molecular basis and pathogenesis of DMD, major gaps remain in understanding mechanisms that contribute to the marked delay in cardiac compared to skeletal muscle dysfunction.MethodsTo address this question, we analyzed cardiac and skeletal muscle tissue microarrays from golden retriever muscular dystrophy (GRMD) dogs, a genetically and clinically homologous model for DMD. A total of 15 dogs, 3 each GRMD and controls at 6 and 12 months plus 3 older (47–93 months) GRMD dogs, were assessed.ResultsGRMD dogs exhibited tissue- and age-specific transcriptional profiles and enriched functions in skeletal but not cardiac muscle, consistent with a “metabolic crisis” seen with DMD microarray studies. Most notably, dozens of energy production-associated molecules, including all of the TCA cycle enzymes and multiple electron transport components, were down regulated. Glycolytic and glycolysis shunt pathway-associated enzymes, such as those of the anabolic pentose phosphate pathway, were also altered, in keeping with gene expression in other forms of muscle atrophy. On the other hand, GRMD cardiac muscle genes were enriched in nucleotide metabolism and pathways that are critical for neuromuscular junction maintenance, synaptic function and conduction.ConclusionsThese findings suggest differential metabolic dysfunction may contribute to distinct pathological phenotypes in skeletal and cardiac muscle.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-017-0257-2) contains supplementary material, which is available to authorized users.

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“…This is likely an important finding, given the previously suggested role of GLUT4 alterations in insulin resistance in DMD patients [30]. …”

Section: Resultssupporting

confidence: 56%

GRMD cardiac and skeletal muscle metabolism gene profiles are distinct

et al. 2017

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“…Nondystrophic obese children (10.7 ± 1.2 years of age) display lower values of whole‐body BD (0.88 vs. 0.96 g/cm 2 ; P < 0.05) and bone mineral content (1,190.98 vs. 1,510.24 g; P < 0.01) than controls . Importantly, obesity has also been reported in 54% of 13‐year‐old patients with DMD …”

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confidence: 95%

“…17 Importantly, obesity has also been reported in 54% of 13-year-old patients with DMD. [18][19][20] Identification of factors associated with bone density loss may be useful to develop strategies focused on optimizing bone health and decreasing the risk of fractures in patients with DMD. Thus, the aim of this study was to identify which factor (muscle weakness, chronic inflammation, or adiposity) plays the most prominent role in BD loss in DMD.…”

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confidence: 99%

Muscle function and age are associated with loss of bone mineral density in Duchenne muscular dystrophy

et al. 2019

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Introduction: Patients with Duchenne muscular dystrophy (DMD) demonstrate decreased bone mineral density (BD). It is not clear which factors exert the greatest impact on BD loss in these patients. Methods: In 63 patients with DMD, serum cytokines (interleukin [IL]‐1, IL‐6, and tumor necrosis factor‐beta [TNF‐β]), C‐reactive protein (CRP), creatine kinase (CK), muscle function (by Vignos scale), body composition, and total BD (the latter 2 measured by dual‐energy X‐ray absorptiometry, or DEXA) were determined. Results: The main factors associated with BD loss were muscle function (34.0%; β = −0.139; P < 0.023) and age (36.7%; β = −0.151; P = 0.004). Cytokines, CRP, body fat mass, and CK did not contribute to BD loss. Discussion: Muscle function and age contribute to BD loss in DMD. We propose that a cut‐off of at least 6 points for the Vignos scale and at least 10.5 years of age predict a Z‐score of less than or equal to −2.0. Muscle Nerve 59:417–421, 2019

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“…PI3K-Akt signaling is transmitted via the insulin receptor, and reduced activity of this pathway causes muscle atrophy, and largely contributes to the development of insulin resistance in type-2 diabetes 3-6 . A similar reduction in insulin sensitivity 7,8 is often caused by the dissociation of dystrophin glycoprotein complex (DGC) in Duchenne muscular dystrophy (DMD) 9,10 , although the precise mechanism is unknown. Specifically, it is unclear how the integrity of the pivotal structural unit of skeletal muscle, the DGC, affects insulin-PI3K-Akt signaling.…”

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confidence: 99%

“…For example, β-dystroglycan association with the ECM protein laminin stimulates PI3K-Akt and MAPK signaling in skeletal muscle 12,16 and IGF-1 activity in differentiating oligodendrocyte 15 . Conversely, DGC dissociation in muscles from DMD patients often correlates with the development of insulin resistance 7,8 . Furthermore, reduced DGC integrity in tumor-bearing mice induces the expression of atrophy-related genes and promotes muscle wasting 14 .…”

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confidence: 99%

Novel signaling hub of insulin receptor, dystrophin glycoprotein complex and plakoglobin regulates muscle size

Mutlak

Aweida

Volodin

et al. 2019

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Signaling through the insulin receptor governs central physiological functions related to cell growth and metabolism. Here we show by tandem native protein complex purification approach and super-resolution STED microscopy that insulin receptor activity requires association with the fundamental structural module in muscle, the dystrophin glycoprotein complex (DGC), and the desmosomal component plakoglobin (g-catenin).The integrity of this high-molecular-mass assembly renders skeletal muscle susceptibility to insulin because DGC-insulin receptor dissociation by plakoglobin downregulation reduced insulin signaling and caused atrophy. Furthermore, impaired insulin receptor function in muscles from diabetic mice reduced plakoglobin-DGC-insulin receptor content on the plasma membrane; however, plakoglobin overexpression alone restored DGC association with the insulin receptor, and stimulated glucose uptake. Our findings establish DGC as a signaling hub, containing plakoglobin as an auxiliary subunit, and provide a possible mechanism for the insulin resistance in Duchenne Muscular Dystrophy, and for the cardiomyopathies seen with plakoglobin mutations.

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Evidence of Insulin Resistance and Other Metabolic Alterations in Boys with Duchenne or Becker Muscular Dystrophy

Cited by 55 publications

References 27 publications

GRMD cardiac and skeletal muscle metabolism gene profiles are distinct

GRMD cardiac and skeletal muscle metabolism gene profiles are distinct

Muscle function and age are associated with loss of bone mineral density in Duchenne muscular dystrophy

Novel signaling hub of insulin receptor, dystrophin glycoprotein complex and plakoglobin regulates muscle size

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