Dataset Information

Phosphatidylinositol 3-kinase inhibition restores Ca2+ release defects and prolongs survival in myotubularin-deficient mice.

ABSTRACT: Mutations in the gene encoding the phosphoinositide 3-phosphatase myotubularin (MTM1) are responsible for a pediatric disease of skeletal muscle named myotubular myopathy (XLMTM). Muscle fibers from MTM1-deficient mice present defects in excitation-contraction (EC) coupling likely responsible for the disease-associated fatal muscle weakness. However, the mechanism leading to EC coupling failure remains unclear. During normal skeletal muscle EC coupling, transverse (t) tubule depolarization triggers sarcoplasmic reticulum (SR) Ca²⁺ release through ryanodine receptor channels gated by conformational coupling with the t-tubule voltage-sensing dihydropyridine receptors. We report that MTM1 deficiency is associated with a 60% depression of global SR Ca²⁺ release over the full range of voltage sensitivity of EC coupling. SR Ca²⁺ release in the diseased fibers is also slower than in normal fibers, or delayed following voltage activation, consistent with the contribution of Ca²⁺-gated ryanodine receptors to EC coupling. In addition, we found that SR Ca²⁺ release is spatially heterogeneous within myotubularin-deficient muscle fibers, with focally defective areas recapitulating the global alterations. Importantly, we found that pharmacological inhibition of phosphatidylinositol 3-kinase (PtdIns 3-kinase) activity rescues the Ca²⁺ release defects in isolated muscle fibers and increases the lifespan and mobility of XLMTM mice, providing proof of concept for the use of PtdIns 3-kinase inhibitors in myotubular myopathy and suggesting that unbalanced PtdIns 3-kinase activity plays a critical role in the pathological process.

SUBMITTER: Kutchukian C

PROVIDER: S-EPMC5167204 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Phosphatidylinositol 3-kinase inhibition restores Ca2+ release defects and prolongs survival in myotubularin-deficient mice.

Kutchukian Candice C Lo Scrudato Mirella M Tourneur Yves Y Poulard Karine K Vignaud Alban A Berthier Christine C Allard Bruno B Lawlor Michael W MW Buj-Bello Ana A Jacquemond Vincent V

Proceedings of the National Academy of Sciences of the United States of America 20161128 50

Mutations in the gene encoding the phosphoinositide 3-phosphatase myotubularin (MTM1) are responsible for a pediatric disease of skeletal muscle named myotubular myopathy (XLMTM). Muscle fibers from MTM1-deficient mice present defects in excitation-contraction (EC) coupling likely responsible for the disease-associated fatal muscle weakness. However, the mechanism leading to EC coupling failure remains unclear. During normal skeletal muscle EC coupling, transverse (t) tubule depolarization trigg ...[more]

PMID: 27911767

Similar Datasets

Project description:SLC19A3 deficiency, also called thiamine metabolism dysfunction syndrome-2 (THMD2; OMIM 607483), is an autosomal recessive neurodegenerative disorder caused by mutations in SLC19A3, the gene encoding thiamine transporter 2. To investigate the molecular mechanisms of neurodegeneration in SLC19A3 deficiency and whether administration of high-dose thiamine prevents neurodegeneration, we generated homozygous Slc19a3 E314Q knock-in (KI) mice harboring the mutation corresponding to the human SLC19A3 E320Q, which is associated with the severe form of THMD2. Homozygous KI mice and previously reported homozygous Slc19a3 knock-out (KO) mice fed a thiamine-restricted diet (thiamine: 0.60 mg/100 g food) died within 30 and 12 days, respectively, with dramatically decreased thiamine concentration in the blood and brain, acute neurodegeneration, and astrogliosis in the submedial nucleus of the thalamus and ventral anterior-lateral complex of the thalamus. These findings may bear some features of thiamine-deficient mice generated by pyrithiamine injection and a thiamine-deficient diet, suggesting that the primary cause of THMD2 could be thiamine pyrophosphate (TPP) deficiency. Next, we analyzed the therapeutic effects of high-dose thiamine treatment. When the diet was reverted to a conventional diet (thiamine: 1.71 mg/100 g food) after thiamine restriction, all homozygous KO mice died. In contrast, when the diet was changed to a high-thiamine diet (thiamine: 8.50 mg/100 g food) after thiamine restriction, more than half of homozygous KO mice survived, without progression of brain lesions. Unexpectedly, when the high-thiamine diet of recovered mice was reverted to a conventional diet, some homozygous KO mice died. These results showed that acute neurodegeneration caused by thiamine deficiency is preventable in most parts, and prompt high-dose thiamine administration is critical for the treatment of THMD2. However, reduction of thiamine should be performed carefully to prevent recurrence after recovery of the disease.

Dataset Information

Phosphatidylinositol 3-kinase inhibition restores Ca2+ release defects and prolongs survival in myotubularin-deficient mice.

Publications

Phosphatidylinositol 3-kinase inhibition restores Ca2+ release defects and prolongs survival in myotubularin-deficient mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets