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      Moderate exercise improves function and increases adiponectin in the mdx mouse model of muscular dystrophy

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          Abstract

          The loss of dystrophin produces a mechanically fragile sarcolemma, causing muscle membrane disruption and muscle loss. The degree to which exercise alters muscular dystrophy has been evaluated in humans with Duchenne Muscular Dystrophy (DMD) and in mouse models including the mdx mouse but with inconsistent findings. We now examined two different levels of exercise, moderate and low intensity, in the mdx mouse model in the DBA2J background. mdx mice at 4–5 months of age were subjected to two different doses of exercise. We found a dose-dependent benefit for low and moderate exercise, defined as 4 m/min or 8 m/min, for 30 minutes three times a week. After six months, exercised mdx mice showed improved tetanic and specific force compared to the sedentary group. We also observed increased respiratory capacity manifesting as greater minute volume, as well as enhanced cardiac function mitigating the decline of fractional shortening that is normally seen. Exercised mdx mice also showed a dose-dependent increase in serum adiponectin with a concomitant reduced adipocyte cross sectional area. These findings identify moderate intensity exercise as a means to improve muscle performance in the mdx DBA2J mice and suggest serum adiponectin as a biomarker for beneficial exercise effect in DMD.

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          Adiponectin: action, regulation and association to insulin sensitivity.

          Adiponectin is a novel adipocyte-specific protein, which, it has been suggested, plays a role in the development of insulin resistance and atherosclerosis. Although it circulates in high concentrations, adiponectin levels are lower in obese subjects than in lean subjects. Apart from negative correlations with measures of adiposity, adiponectin levels are also reduced in association with insulin resistance and type 2 diabetes. Visceral adiposity has been shown to be an independent negative predictor of adiponectin. Thus, most features of the metabolic syndrome's negative associations with adiponectin have been shown. Adiponectin levels seem to be reduced prior to the development of type 2 diabetes, and administration of adiponectin has been accompanied by lower plasma glucose levels as well as increased insulin sensitivity. Furthermore, reduced expression of adiponectin has been associated with some degree of insulin resistance in animal studies indicating a role for hypoadiponectinaemia in relation to insulin resistance. The primary mechanisms by which adiponectin enhance insulin sensitivity appears to be through increased fatty acid oxidation and inhibition of hepatic glucose production. Adiponectin levels are increased by thiazoledinedione treatment, and this effect might be important for the enhanced insulin sensitivity induced by thiazolidinediones. In contrast, adiponectin levels are reduced by pro-inflammatory cytokines especially tumour necrosis factor-alpha. In summary, adiponectin in addition to possible anti-inflammatory and anti-atherogenic effects appears to be an insulin enhancer, with potential as a new pharmacologic treatment modality of the metabolic syndrome and type 2 diabetes.
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            Eteplirsen treatment for Duchenne muscular dystrophy

            To describe the quantification of novel dystrophin production in patients with Duchenne muscular dystrophy (DMD) after long-term treatment with eteplirsen.
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              Effect of genetic background on the dystrophic phenotype in mdx mice.

              Genetic background significantly affects phenotype in multiple mouse models of human diseases, including muscular dystrophy. This phenotypic variability is partly attributed to genetic modifiers that regulate the disease process. Studies have demonstrated that introduction of the γ-sarcoglycan-null allele onto the DBA/2J background confers a more severe muscular dystrophy phenotype than the original strain, demonstrating the presence of genetic modifier loci in the DBA/2J background. To characterize the phenotype of dystrophin deficiency on the DBA/2J background, we created and phenotyped DBA/2J-congenic Dmdmdx mice (D2-mdx) and compared them with the original, C57BL/10ScSn-Dmdmdx (B10-mdx) model. These strains were compared with their respective control strains at multiple time points between 6 and 52 weeks of age. Skeletal and cardiac muscle function, inflammation, regeneration, histology and biochemistry were characterized. We found that D2-mdx mice showed significantly reduced skeletal muscle function as early as 7 weeks and reduced cardiac function by 28 weeks, suggesting that the disease phenotype is more severe than in B10-mdx mice. In addition, D2-mdx mice showed fewer central myonuclei and increased calcifications in the skeletal muscle, heart and diaphragm at 7 weeks, suggesting that their pathology is different from the B10-mdx mice. The new D2-mdx model with an earlier onset and more pronounced dystrophy phenotype may be useful for evaluating therapies that target cardiac and skeletal muscle function in dystrophin-deficient mice. Our data align the D2-mdx with Duchenne muscular dystrophy patients with the LTBP4 genetic modifier, making it one of the few instances of cross-species genetic modifiers of monogenic traits.
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                Author and article information

                Contributors
                elizabeth.mcnally@northwestern.edu
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                8 April 2019
                8 April 2019
                2019
                : 9
                : 5770
                Affiliations
                [1 ]ISNI 0000 0001 2299 3507, GRID grid.16753.36, Center for Genetic Medicine, Feinberg School of Medicine, , Northwestern University, ; Chicago, IL USA
                [2 ]ISNI 0000 0004 0388 2248, GRID grid.413808.6, Ann and Robert H. Lurie Children’s Hospital of Chicago, ; Chicago, IL USA
                [3 ]ISNI 0000 0001 2287 3919, GRID grid.257413.6, Indiana University School of Medicine, ; Indianapolis, IN USA
                Article
                42203
                10.1038/s41598-019-42203-z
                6453911
                30962487
                8f25bd63-c89c-4e4b-875f-05da6216353a
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 17 September 2018
                : 27 March 2019
                Funding
                Funded by: FundRef https://doi.org/10.13039/100005693, Parent Project Muscular Dystrophy (Parent Project for Muscular Dystrophy Research, Inc.);
                Funded by: FundRef https://doi.org/10.13039/100005202, Muscular Dystrophy Association (Muscular Dystrophy Association Inc.);
                Award ID: 479350
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000062, U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (National Institute of Diabetes & Digestive & Kidney Diseases);
                Award ID: DK007169
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000069, U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS);
                Award ID: AR052646
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000050, U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI);
                Award ID: HL061322
                Award Recipient :
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