Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
Proc Natl Acad Sci U S A. 2013 Aug 13;110(33):13570-5. doi: 10.1073/pnas.1308806110. Epub 2013 Jul 30.
Myotonic dystrophy type 1 (DM1) is caused by expansion of CTG repeats in the 3' UTR of the DMPK gene. Expression of CUG expansion (CUG(exp)) RNA produces a toxic gain of function by disrupting the functions of RNA splicing factors, such as MBNL1 and CELF1, leading to splicing changes associated with clinical abnormalities. Progressive skeletal muscle weakness and wasting is one of the most prominent clinical features in DM1; however, the underlying mechanisms remain unclear. Here we report that the embryonic M2 isoform of pyruvate kinase (PKM2), a key enzyme contributing to the Warburg effect in cancer, is significantly induced in DM1 tissue and mouse models owing to aberrant splicing. Expression of PKM2 in DM1 skeletal muscle is restricted to the type 1 fibers, which are particularly susceptible to wasting in DM1. Using antisense oligonucleotides to shift PKM splicing toward increased PKM2 expression, we observed increased glucose consumption with reduced oxidative metabolism in cell culture and increased respiratory exchange ratio in mice, suggesting defects in energy metabolism conferred by PKM2 expression. We propose that PKM2 expression induces changes in type 1 fibers associated with muscle atrophy and muscle weakness in DM1.
肌强直性营养不良 1 型（DM1）是由 DMPK 基因 3'UTR 中的 CTG 重复扩展引起的。CUG 扩展（CUG(exp)) RNA 的表达通过破坏 RNA 剪接因子（如 MBNL1 和 CELF1）的功能产生毒性获得功能，导致与临床异常相关的剪接变化。进行性骨骼肌无力和消瘦是 DM1 最突出的临床特征之一；然而，其潜在机制仍不清楚。在这里，我们报告由于剪接异常，丙酮酸激酶（PKM）的胚胎 M2 同工型（PKM2）在 DM1 组织和小鼠模型中显著诱导，PKM2 是参与癌症中瓦博格效应的关键酶。由于剪接异常，DM1 骨骼肌中 PKM2 的表达仅限于特别容易发生消瘦的 1 型纤维。使用反义寡核苷酸将 PKM 剪接向增加的 PKM2 表达转移，我们观察到细胞培养中葡萄糖消耗增加，氧化代谢减少，以及在小鼠中呼吸交换率增加，这表明 PKM2 表达引起的能量代谢缺陷。我们提出 PKM2 的表达诱导与 DM1 中肌肉萎缩和肌肉无力相关的 1 型纤维变化。
