Annane D, Duboc D, Mazoyer B, Merlet P, Fiorelli M, Eymard B, Radvanyi H, Junien C, Fardeau M, Gajdos P
Service Hospitalier Frédéric Joliot, CEA, Orsay, France.
Circulation. 1994 Dec;90(6):2629-34. doi: 10.1161/01.cir.90.6.2629.
Myotonic dystrophy, the most common form of adult dystrophy, has been shown to be caused by amplification of CTG triplet repeat in the 3' untranslated region of a protein kinase gene located on chromosome 19. Impaired glucose metabolism has been suggested as a possible explanation of brain and skeletal muscle involvement in this multisystem disease. We investigated whether myocardial glucose metabolism is impaired in myotonic dystrophy and whether this impairment is related to the size of the mutation.
The myocardial metabolic rate for glucose (MMRGlu, mumol.min-1.g-1), K1 (blood-to-tissue transfer constant), k2 (tissue-to-blood transfer constant), and k3 (phosphorylation rate constant) were determined in 7 control subjects and 12 patients with myotonic dystrophy by using parametric images generated from dynamic cardiac positron emission tomography (PET) and 18F-fluoro-2-deoxy-glucose studies. The expansion of the CTG triplet repeats was analyzed in patients with the probe cDNA25 after EcoRI digestion. Nonparametric tests were used to compare quantitative variables between control subjects and patients. The correlations between the size of the mutation and PET parameters were studied by linear regression. MMRGlu and k3 were significantly decreased in patients compared with control subjects (0.39 +/- 0.20 versus 0.64 +/- 0.25, P = .03, and 0.09 +/- 0.07 versus 0.24 +/- 0.21, P = .03, respectively), whereas K1 and k2 were not statistically different between control subjects and patients. MMRGlu and k3 correlate inversely with the length of the CTG triplet repeat (r = -.65 and P = .03 for MMRGlu, and r = -.85 and P = .001 for k3, respectively).
In myotonic dystrophy, the observed reductions in MMRGlu and phosphorylation are inversely linked to the length of the mutation. This observation suggests that impaired modulation of a protein kinase involved in myocardial hexokinase activation may give a pathophysiological schema to relate the molecular defect and the abnormal myocardial metabolism in myotonic dystrophy.
强直性肌营养不良是成人肌营养不良最常见的形式，已证实其由位于19号染色体上的蛋白激酶基因3'非翻译区CTG三联体重复序列扩增所致。葡萄糖代谢受损被认为可能是这种多系统疾病中脑和骨骼肌受累的一种解释。我们研究了强直性肌营养不良患者的心肌葡萄糖代谢是否受损，以及这种损害是否与突变大小有关。
通过动态心脏正电子发射断层扫描（PET）和18F-氟-2-脱氧葡萄糖研究生成的参数图像，测定了7名对照受试者和12名强直性肌营养不良患者的心肌葡萄糖代谢率（MMRGlu，μmol·min-1·g-1）、K1（血-组织转运常数）、k2（组织-血转运常数）和k3（磷酸化速率常数）。用EcoRI消化后，用探针cDNA25分析患者的CTG三联体重复序列扩增情况。采用非参数检验比较对照受试者和患者之间的定量变量。通过线性回归研究突变大小与PET参数之间的相关性。与对照受试者相比，患者的MMRGlu和k3显著降低（分别为0.39±0.20对0.64±0.25，P = 0.03；0.09±0.07对0.24±0.21，P = 0.03），而对照受试者和患者之间的K1和k2无统计学差异。MMRGlu和k3与CTG三联体重复序列长度呈负相关（MMRGlu的r = -0.65，P = 0.03；k3的r = -0.85，P = 0.001）。
在强直性肌营养不良中，观察到的MMRGlu降低和磷酸化与突变长度呈负相关。这一观察结果表明，参与心肌己糖激酶激活的蛋白激酶调节受损可能为强直性肌营养不良中分子缺陷与异常心肌代谢之间的病理生理关系提供一个模式。
