Manipulation of PK-M mutually exclusive alternative splicing by antisense oligonucleotides

Wang, Zhenxun; Jeon, Hyun Yong; Rigo, Frank; Bennett, C. Frank; Krainer, Adrian R.

doi:10.1098/rsob.120133

Cited by 55 publications

(48 citation statements)

References 31 publications

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“…S3). A minor product indicating skipping of both exons 9 and 10 was also observed, as described previously (23,31). Western blot analysis verified the substantial decrease (∼5-to 10-fold) in Pkm1 with a concomitant increase (∼5-to 10-fold) in Pkm2 (Fig.…”

Section: A Splicing Shift To Pkm2 Alters Glucose Metabolism In Culturedmentioning

confidence: 58%

Reexpression of pyruvate kinase M2 in type 1 myofibers correlates with altered glucose metabolism in myotonic dystrophy

Gao

Cooper

2013

Proc. Natl. Acad. Sci. U.S.A.

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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. muscular dystrophy | redirected splicing | striated muscle development | alternative splicing M yotonic dystrophy (DM) is the most common adult-onset form of muscular dystrophy (1, 2). It is caused by expanded CTG repeats in the 3′ UTR of the DMPK gene (type 1; DM1) or expanded CCTG repeats in the first intron of the CNBP gene (type 2; DM2) (3-5). The RNAs transcribed from the expanded CTG or CCTG alleles produce a dominant toxic gain of function (2, 6). The toxicity of CUG-and CCUG-expanded RNAs (CUG exp and CCUG exp RNA) involves two main pathogenic mechanisms. First, CUG exp or CCUG exp RNAs bind and sequester muscleblindlike (MBNL) proteins within ribonuclear foci, resulting in MBNL loss of function (7,8). Second, CUG exp RNA activates protein kinase C, which phosphorylates and stabilizes CELF1, resulting in its elevation and gain of function (9). MBNL and CELF1 proteins regulate alternative splicing during development, and disruption of their functions leads to aberrant splicing transitions implicated in such manifestations of DM as myotonia and insulin resistance (2).Progressive muscle weakness and wasting are among the most prominent clinical features of DM1 (1). In contrast to other forms of muscular dystrophy, such as Duchenne muscular dystrophy, the muscle weakness and wasting in DM1 is not accompanied by overt regeneration, fibrosis and necrosis. Instead, the most prominent histological abnormalities in DM1 are centralized nuclei and slow myofiber (type 1 fiber) atrophy (1). Early studies suggested that reduced protein synthesis and an imbalance of anabolism and catabolism may be responsible for the muscle wasting in DM1 (10, 11). Recent studies have shown that abnormal T-tubule biogenesis and calcium signaling, along with increased glycogen synthase kinase 3β (GSK3β) ...

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Section: A Splicing Shift To Pkm2 Alters Glucose Metabolism In Culturedmentioning

confidence: 58%

Reexpression of pyruvate kinase M2 in type 1 myofibers correlates with altered glucose metabolism in myotonic dystrophy

Gao

Cooper

2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Serum glucose is needed for cancer cell growth, as cancerous cells are switched to obtaining energy from aerobic glycolysis, the Warburg effect. Cancerous cells use the intermediates of the glycolytic pathway to generate FA and other biosynthetic intermediates within the cell so as to generate cell membranes and organelles and thereby allow cell growth and division, and this is what most of the glucose is used for (Warburg 1956;Wang et al 2012). Paradoxically, these cells do not derive much energy from either ketone bodies or b-oxidation of FA, irrespective of the circulating level of FA.…”

Section: Health Effects Of Fat As a Macronutrient And Energy Sourcementioning

confidence: 99%

Should animal fats be back on the table? A critical review of the human health effects of animal fat

Barendse

2014

Anim. Prod. Sci.

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Abstract.Humans hunt or raise a wide variety of animals for meat, which vary from free-range to intensively reared. These animals form a valuable part of human nutrition. Their tissues, including the fat, contain vitamin and other essential nutrients necessary for health. However, animal fat from ruminants and other land mammals is usually regarded as saturated. The purpose of this review is partly to examine the basis for the saturated fat hypothesis of cardiovascular disease given more recent research, to examine the human health effects of animal fats, and partly to draw into one place the diverse knowledge about animal fat and the effects of fat on metabolism. Mechanistic understanding of the initiation of the fatty streak and atherosclerosis calls into question the avoidance of ruminant or porcine fat. Due to high levels of oleic acid, a low n-6 : n-3 fatty acid ratio in some groups, and the presence of specific micronutrients including vitamins and essential fatty acids, animal fats are of benefit in human nutrition. Animal fats can be obtained in minimally processed form making them a convenient source of energy and micronutrients.

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“…169 Cancer treatment based on splicing modulation has also been attempted. To date, several targets have been studied, such as RON, 170 PKM, 171 Mdm, 172 mcl-1, 173 FGFR1, 174 and BCL-X. 175 For a further review on ASO-based treatment please see.…”

Section: Targeted Modulation Of Splicing By Antisense Oligonucleotidesmentioning

confidence: 99%

The role of splicing factors in deregulation of alternative splicing during oncogenesis and tumor progression

Shilo

Siegfried

Karni

2014

Molecular & Cellular Oncology

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In past decades, cancer research has focused on genetic alterations that are detected in malignant tissues and contribute to the initiation and progression of cancer. These changes include mutations, copy number variations, and translocations. However, it is becoming increasingly clear that epigenetic changes, including alternative splicing, play a major role in cancer development and progression. There are relatively few studies on the contribution of alternative splicing and the splicing factors that regulate this process to cancer development and progression. Recently, multiple studies have revealed altered splicing patterns in cancers and several splicing factors were found to contribute to tumor development. Studies using high-throughput genomic analysis have identified mutations in components of the core splicing machinery and in splicing factors in several cancers. In this review, we will highlight new findings on the role of alternative splicing and its regulators in cancer initiation and progression, in addition to novel approaches to correct oncogenic splicing.

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Manipulation of PK-M mutually exclusive alternative splicing by antisense oligonucleotides

Cited by 55 publications

References 31 publications

Reexpression of pyruvate kinase M2 in type 1 myofibers correlates with altered glucose metabolism in myotonic dystrophy

Reexpression of pyruvate kinase M2 in type 1 myofibers correlates with altered glucose metabolism in myotonic dystrophy

Should animal fats be back on the table? A critical review of the human health effects of animal fat

The role of splicing factors in deregulation of alternative splicing during oncogenesis and tumor progression

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