title: Reexpression of pyruvate kinase M2 in type 1 myofibers correlates with altered glucose metabolism in myotonic dystrophy.
abstract: 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.
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Gao
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Cooper
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D015153:Blotting, Western; D002153:Calorimetry, Indirect; D002460:Cell Line; D004734:Energy Metabolism / Q000235:genetics*; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D019344:Lactic Acid / Q000378:metabolism; D051379:Mice; D018657:Muscle Fibers, Slow-Twitch / Q000378:metabolism* / Q000473:pathology; D009223:Myotonic Dystrophy / Q000201:enzymology*; D020320:Oligoribonucleotides, Antisense / Q000235:genetics; D010101:Oxygen Consumption / Q000502:physiology; D011770:Pyruvate Kinase / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D020320:Oligoribonucleotides, Antisense; D019344:Lactic Acid; D011770:Pyruvate Kinase; D005947:Glucose
keywords: alternative splicing; muscular dystrophy; redirected splicing; striated muscle development
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