Mechanism of muscle wasting in myotonic dystrophy

Griggs, Robert C.; Józefowicz, Ralph F.; Kingston, William J.; Nair, K. Sreekumaran; Herr, Barbara E.; Halliday, D.

doi:10.1002/ana.410270509

Cited by 24 publications

(17 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is unlikely that changes in a single splicing event, such as PKM2 expression, would result in the progressive muscle weakness; however, multiple splicing defects in the same signaling or metabolic pathway may accumulate to disrupt muscle function. Given the importance of insulin signaling in protein synthesis and anabolism, the previously reported aberrant splicing of insulin receptors (15) likely results in deficient protein synthesis in skeletal muscle, in agreement with earlier studies suggesting that the muscle weakness in DM1 results from a reduced protein synthesis rate (11). The expression of PKM2 in DM1 muscle can further perturb glucose metabolism and energy homeostasis.…”

Section: Discussionsupporting

confidence: 88%

“…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) activity, are associated with muscle weakness (12)(13)(14).…”

mentioning

confidence: 99%

See 1 more Smart Citation

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.

View full text Add to dashboard Cite

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) ...

show abstract

Section: Discussionsupporting

confidence: 88%

mentioning

confidence: 99%

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.

View full text Add to dashboard Cite

show abstract

“…The myopathy in DM1 has been attributed to factors including altered: (a) protein synthesis [38] (b) contractile protein expression and force generating capacity [39, 40], (c) Ca 2+ -calmodulin-dependent protein kinase activity and phosphorylation of phospholamban [39] and (d) ATP turnover [41]. Additionally, while ASI(-)RyR1 expression is increased in DM1, the mechanism by which lowered resting RyR1 channel activity could contribute to the myopathy was unclear [5].…”

Section: 0 Discussionmentioning

confidence: 99%

Alternative splicing of RyR1 alters the efficacy of skeletal EC coupling

Kimura¹,

Lueck²,

Harvey³

et al. 2009

Cell Calcium

View full text Add to dashboard Cite

SummaryAlternative splicing of ASI residues (Ala 3481 -Gln 3485 ) in the skeletal muscle ryanodine receptor (RyR1) is developmentally regulated: the residues are present in adult ASI(+)RyR1, but absent in the juvenile ASI(-)RyR1 which is over-expressed in adult myotonic dystrophy type 1 (DM1). Although this splicing switch may influence RyR1 function in developing muscle and DM1, little is known about the properties of the splice variants. We examined excitation-contraction (EC) coupling and the structure and interactions of the ASI domain (Thr 3471 -Gly 3500 ) in the splice variants. Depolarisation-dependent Ca 2+ release was enhanced by >50% in myotubes expressing ASI(-)RyR1 compared with ASI(+)RyR1, although DHPR L-type currents and SR Ca 2+ content were unaltered, while ASI(-)RyR1 channel function was actually depressed. The effect on EC coupling did not depend on changes in ASI domain secondary structure. Probing RyR1 function with peptides possessing the ASI domain sequence indicated that the domain contributes to an inhibitory module in RyR1. The action of the peptide depended on a sequence of basic residues and their alignment in an α-helix adjacent to the ASI splice site. This is the first evidence that the ASI residues contribute to an inhibitory module in RyR1 that influences EC coupling. Implications for development and DM1 are discussed.

show abstract

“…Some older studies suggest that muscle wasting in patients with DM1 is caused by a defect in the muscle protein synthesis rather than by a defect in accelerated muscle breakdown (11,12). In contrast, another study found that muscle wasting is caused by an elevated protein breakdown in DM1 patients, which could be explained by lower levels of plasma IGF-1 and higher levels of TNF-␣ (20).…”

Section: Discussionmentioning

confidence: 99%

Protein-carbohydrate supplements improve muscle protein balance in muscular dystrophy patients after endurance exercise: a placebo-controlled crossover study

Andersen

Ørngreen

Preisler

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

View full text Add to dashboard Cite

Andersen G, Ørngreen MC, Preisler N, Jeppesen TD, Krag TO, Hauerslev S, van Hall G, Vissing J. Protein-carbohydrate supplements improve muscle protein balance in muscular dystrophy patients after endurance exercise: a placebo-controlled crossover study. Am J Physiol Regul Integr Comp Physiol 308: R123-R130, 2015. First published November 19, 2014 doi:10.1152/ajpregu.00321.2014.-In healthy individuals, postexercise protein supplementation increases muscle protein anabolism. In patients with muscular dystrophies, aerobic exercise improves muscle function, but the effect of exercise on muscle protein balance is unknown. Therefore, we investigated 1) muscle protein balance before, during, and after exercise and 2) the effect of postexercise protein-carbohydrate supplementation on muscle protein balance in patients with muscular dystrophies. In 17 patients [7 women and 10 men, aged 33 Ϯ 11 yr (18 -52), body mass index: 22 Ϯ 3 kg/m 2 (16 -26)] and 8 healthy matched controls [3 women and 5 men, age 33 Ϯ 13 years (19 -54), body mass index: 23 Ϯ 3 kg/m 2 (19 -27)], muscle protein synthesis, breakdown, and fractional synthesis rates (FSR) were measured across the leg using tracer dilution methodology on two occasions, with and without oral postexercise protein-carbohydrate supplementation. In patients, muscle protein breakdown increased in the recovery period (11 Ϯ 1 mol phenylalanine/min) vs. rest (8 Ϯ 1 mol phenylalanine/min, P ϭ 0.02), enhancing net muscle protein loss. In contrast, postexercise protein-carbohydrate supplementation reduced protein breakdown, abolished net muscle protein loss, and increased the muscle FSR in patients (0.04 to 0.06%/h; P ϭ 0.03). In conclusion, postexercise protein-carbohydrate supplementation reduces skeletal mixed-muscle protein breakdown, enhances FSR, resulting in a reduced net muscle loss in patients with muscular dystrophies. The findings suggest that postexercise protein-carbohydrate supplementation could be an important add-on to exercise training therapy in muscular dystrophies, and long-term studies of postexercise protein-carbohydrate supplementation are warranted in these conditions. endurance exercise; protein-carbohydrate supplementation; muscle protein metabolism; muscular dystrophy THE MOST COMMON INHERITED muscular dystrophies in adults are myotonic dystrophy type 1 (DM1), facioscapulohumeral muscular dystrophy (FSHD), Becker muscular dystrophy (BMD), and limb girdle muscular dystrophy type 2 I (LGMD2I), which primarily affect skeletal muscle with clinical manifestations of progressive muscle wasting and weakness. No curative treatment exists, but a number of nonspecific, symptomatic treatments are available. Regular cycle exercise at moderate intensity has been shown to be safe and improve fitness and self-reported daily activity levels (18,19,25,26), but muscle protein metabolism during exercise is unknown in these disorders.In healthy individuals, exercise induces an initial net muscle protein breakdown (22), which increases intramuscular concentration of amino acid...

show abstract

Mechanism of muscle wasting in myotonic dystrophy

Cited by 24 publications

References 42 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

Alternative splicing of RyR1 alters the efficacy of skeletal EC coupling

Protein-carbohydrate supplements improve muscle protein balance in muscular dystrophy patients after endurance exercise: a placebo-controlled crossover study

Contact Info

Product

Resources

About