The relationship between clinical stage, prognosis and myocardial damage in patients with Duchenne-type muscular dystrophy: five-year follow-up study

Naruse, Hitoshi; Miyagi, Junko; Arii, Tohru; Ohyanagi, Mitsumasa; Iwasaki, Tadaaki; Jinnai, Kenji

doi:10.1007/bf02985001

Cited by 11 publications

(6 citation statements)

References 25 publications

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“…The metabolic shift from LCFA to CHO that we observed in young mdx mice concurs with findings from cardiac positron emission tomography studies performed in patients with DMD using 18 F-deoxyglucose or a radioiodinated branched fatty acid ( [57][58][59][60]. Although metabolic flux parameters relative to LCFA partitioning between oxidation and triglyceride synthesis were not specifically assessed in our study, our results indicated that the contribution of endogenous substrates (postulated to be triglycerides) to acetyl-CoA production was similar to controls at this early stage of the cardiomyopathic process, presumably because lower LCFA oxidation was compensated by increased CHO oxidation.…”

Section: Alterations In Mitochondrial Substrate Metabolism In the Earsupporting

confidence: 76%

Alterations in mitochondrial function as a harbinger of cardiomyopathy: Lessons from the dystrophic heart

Burelle

Khairallah

Ascah

et al. 2010

Journal of Molecular and Cellular Cardiology

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While compelling evidence supports the central role of mitochondrial dysfunction in the pathogenesis of heart failure, there is comparatively less information available on mitochondrial alterations that occur prior to failure. Building on our recent work with the dystrophin-deficient mdx mouse heart, this review focuses on how early changes in mitochondrial functional phenotype occur prior to overt cardiomyopathy and may be a determinant for the development of adverse cardiac remodelling leading to failure. These include alterations in energy substrate utilization and signalling of cell death through increased permeability of mitochondrial membranes, which may result from abnormal calcium handling, and production of reactive oxygen species. Furthermore, we will discuss evidence supporting the notion that these alterations in the dystrophin-deficient heart may represent an early "subclinical" signature of a defective nitric oxide/cGMP signalling pathway, as well as the potential benefit of mitochondria-targeted therapies. While the mdx mouse is an animal model of Duchenne muscular dystrophy (DMD), changes in the structural integrity of dystrophin, the mutated cytoskeletal protein responsible for DMD, have also recently been implicated as a common mechanism for contractile dysfunction in heart failure. In fact, altogether our findings support a critical role for dystrophin in maintaining optimal coupling between metabolism and contraction in the heart.

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Section: Alterations In Mitochondrial Substrate Metabolism In the Earsupporting

confidence: 76%

Alterations in mitochondrial function as a harbinger of cardiomyopathy: Lessons from the dystrophic heart

Burelle

Khairallah

Ascah

et al. 2010

Journal of Molecular and Cellular Cardiology

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“…Here PDH phosphorylation at three serine residues (pSer232, pSer293, pSer300 in the mouse) on the alpha chain of the E1 subunit is significantly decreased in conjunction with an increase in PDH activity. This increases in PDH activity may account for the previously described elevation in the pyruvate decarboxylation and the shift from fatty acid to carbohydrate oxidation in the heart of both mdx and DMD patients (Perloff et al, 1984;Quinlivan et al, 1996;Momose et al, 2001;Naruse et al, 2004;Khairallah et al, 2007). PDH catalyzes the irreversible step of oxidative decarboxylation of pyruvate to produce acetyl-CoA and fuel the tricarboxylic acid cycle and electron transport chain.…”

Section: Discussionmentioning

confidence: 84%

Metformin Reverses the Enhanced Myocardial SR/ER–Mitochondria Interaction and Impaired Complex I-Driven Respiration in Dystrophin-Deficient Mice

Angebault

Panel

Lacote

et al. 2021

Front. Cell Dev. Biol.

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Besides skeletal muscle dysfunction, Duchenne muscular dystrophy (DMD) exhibits a progressive cardiomyopathy characterized by an impaired calcium (Ca2+) homeostasis and a mitochondrial dysfunction. Here we aimed to determine whether sarco-endoplasmic reticulum (SR/ER)–mitochondria interactions and mitochondrial function were impaired in dystrophic heart at the early stage of the pathology. For this purpose, ventricular cardiomyocytes and mitochondria were isolated from 3-month-old dystrophin-deficient mice (mdx mice). The number of contacts points between the SR/ER Ca2+ release channels (IP3R1) and the porine of the outer membrane of the mitochondria, VDAC1, measured using in situ proximity ligation assay, was greater in mdx cardiomyocytes. Expression levels of IP3R1 as well as the mitochondrial Ca2+ uniporter (MCU) and its regulated subunit, MICU1, were also increased in mdx heart. MICU2 expression was however unchanged. Furthermore, the mitochondrial Ca2+ uptake kinetics and the mitochondrial Ca2+ content were significantly increased. Meanwhile, the Ca2+-dependent pyruvate dehydrogenase phosphorylation was reduced, and its activity significantly increased. In Ca2+-free conditions, pyruvate-driven complex I respiration was decreased whereas in the presence of Ca2+, complex I-mediated respiration was boosted. Further, impaired complex I-mediated respiration was independent of its intrinsic activity or expression, which remains unchanged but is accompanied by an increase in mitochondrial reactive oxygen species production. Finally, mdx mice were treated with the complex I modulator metformin for 1 month. Metformin normalized the SR/ER-mitochondria interaction, decreased MICU1 expression and mitochondrial Ca2+ content, and enhanced complex I-driven respiration. In summary, before any sign of dilated cardiomyopathy, the DMD heart displays an aberrant SR/ER-mitochondria coupling with an increase mitochondrial Ca2+ homeostasis and a complex I dysfunction. Such remodeling could be reversed by metformin providing a novel therapeutic perspective in DMD.

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“…The majority of DMD patients develop cardiomyopathy and with the advent of ventilators, heart failure is emerging as the leading cause of mortality [3–5]. Cardiomyopathy in DMD is characterized by the accumulation of fibrosis which promotes heart dysfunction [6–8]. Perivascular fibrosis, described in many cardiac diseases processes including DMD, has been implicated in heart failure [9, 10].…”

Section: Introductionmentioning

confidence: 99%

Coronary adventitial cells are linked to perivascular cardiac fibrosis via TGFβ1 signaling in the mdx mouse model of Duchenne muscular dystrophy

Ieronimakis¹,

Hays²,

Janebodin³

et al. 2013

Journal of Molecular and Cellular Cardiology

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In Duchenne Muscular Dystrophy (DMD), progressive accumulation of cardiac fibrosis promotes heart failure. While the cellular origins of fibrosis in DMD hearts remain enigmatic, fibrotic tissue conspicuously forms near the coronary adventitia. Therefore, we sought to characterize the role of coronary adventitial cells in the formation of perivascular fibrosis. Utilizing the mdx model of DMD, we have identified a population of Sca1+, PDGFRα+, CD31−, CD45− coronary adventitial cells responsible for perivascular fibrosis. Histopathology of dystrophic hearts revealed Sca1+ cells extend from the adventitia and occupy regions of perivascular fibrosis. The number of Sca1+ adventitial cells increased two-fold in fibrotic mdx hearts vs. age matched wild-type hearts. Moreover, relative to Sca1−, PDGFRα+, CD31−, CD45− cells and endothelial cells, Sca1+ adventitial cells FACS-sorted from mdx hearts expressed the highest level of Collagen1α1 and 3α1, Connective tissue growth factor, and Tgfβr1 transcripts. Surprisingly, mdx endothelial cells expressed the greatest level of the Tgfβ1 ligand. Utilizing Collagen1α1-GFP reporter mice, we confirmed that the majority of Sca1+ adventitial cells expressed type I collagen, an abundant component of cardiac fibrosis, in both wt (71% ±4.1) and mdx (77% ±3.5) hearts. In contrast, GFP+ interstitial fibroblasts were PDGFRα+ but negative for Sca1. Treatment of cultured Collagen1α1-GFP+ adventitial cells with TGFβ1 resulted in increased collagen synthesis, whereas pharmacological inhibition of TGFβR1 signaling reduced the fibrotic response. Therefore, perivascular cardiac fibrosis by coronary adventitial cells may be mediated by TGFβ1 signaling. Our results implicate coronary endothelial cells in mediating cardiac fibrosis via transmural TGFβ signaling, and suggest that the coronary adventitia is a promising target for developing novel anti-fibrotic therapies.

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The relationship between clinical stage, prognosis and myocardial damage in patients with Duchenne-type muscular dystrophy: five-year follow-up study

Abstract: The septum is the critical area of significance for cardiac events and outcome in patients with DMD. The uptake of [201Tl] in this area was representative of the clinical stage, and TL-BM correlated well with the prognosis.

Cited by 11 publications

References 25 publications

Alterations in mitochondrial function as a harbinger of cardiomyopathy: Lessons from the dystrophic heart

Alterations in mitochondrial function as a harbinger of cardiomyopathy: Lessons from the dystrophic heart

Metformin Reverses the Enhanced Myocardial SR/ER–Mitochondria Interaction and Impaired Complex I-Driven Respiration in Dystrophin-Deficient Mice

Coronary adventitial cells are linked to perivascular cardiac fibrosis via TGFβ1 signaling in the mdx mouse model of Duchenne muscular dystrophy

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