Potential Compensatory Mechanisms Preserving Cardiac Function in Myotubular Myopathy

Overview

Journal Cell Mol Life Sci

Publisher Springer

Specialty Biology

Date 2024 Dec 3

PMID 39625536

Authors

Alix Simon

Nadege Diedhiou

David Reiss

Marie Goret

Erwan Grandgirard

Jocelyn Laporte

Affiliations

Soon will be listed here.

Abstract

X-Linked myotubular myopathy (XLMTM) is characterized by severe skeletal muscle weakness and reduced life expectancy. The pathomechanism and the impact of non-muscular defects affecting survival, such as liver dysfunction, are poorly understood. Here, we investigated organ-specific effects of XLMTM using the Mtm1 mouse model. We performed RNA-sequencing to identify a common mechanism in different skeletal muscles, and to explore potential phenotypes and compensatory mechanisms in the heart and the liver. The cardiac and hepatic function and structural integrity were assessed both in vivo and in vitro. Our findings revealed no defects in liver function or morphology. A disease signature common to several skeletal muscles highlighted dysregulation of muscle development, inflammation, cell adhesion and oxidative phosphorylation as key pathomechanisms. The heart displayed only mild functional alterations without obvious structural defects. Transcriptomic analyses revealed an opposite dysregulation of mitochondrial function, cell adhesion and beta integrin trafficking pathways in cardiac muscle compared to skeletal muscles. Despite this dysregulation, biochemical and cellular experiments demonstrated that these pathways were strongly affected in skeletal muscle and normal in cardiac muscle. Moreover, biomarkers reflecting the molecular activity of MTM1, such as PtdIns3P and dynamin 2 levels, were increased in the skeletal muscles but not in cardiac muscle. Overall, these data suggest a compensatory mechanism preserving cardiac function, pointing to potential therapeutic targets to cure the severe skeletal muscle defects in XLMTM.

References

Cocanougher B, Flynn L, Yun P, Jain M, Waite M, Vasavada R . Adult -related myopathy carriers: Classification based on deep phenotyping. Neurology. 2019; 93(16):e1535-e1542. PMC: 6815204. DOI: 10.1212/WNL.0000000000008316. View

Buj-Bello A, Laugel V, Messaddeq N, Zahreddine H, Laporte J, Pellissier J . The lipid phosphatase myotubularin is essential for skeletal muscle maintenance but not for myogenesis in mice. Proc Natl Acad Sci U S A. 2002; 99(23):15060-5. PMC: 524320. DOI: 10.1073/pnas.212498399. View

Hong T, Yang H, Zhang S, Cho H, Kalashnikova M, Sun B . Cardiac BIN1 folds T-tubule membrane, controlling ion flux and limiting arrhythmia. Nat Med. 2014; 20(6):624-32. PMC: 4048325. DOI: 10.1038/nm.3543. View

Laporte J, Hu L, Kretz C, Mandel J, Kioschis P, Coy J . A gene mutated in X-linked myotubular myopathy defines a new putative tyrosine phosphatase family conserved in yeast. Nat Genet. 1996; 13(2):175-82. DOI: 10.1038/ng0696-175. View

Gillespie M, Jassal B, Stephan R, Milacic M, Rothfels K, Senff-Ribeiro A . The reactome pathway knowledgebase 2022. Nucleic Acids Res. 2021; 50(D1):D687-D692. PMC: 8689983. DOI: 10.1093/nar/gkab1028. View

Gomez-Oca R, Cowling B, Laporte J . Common Pathogenic Mechanisms in Centronuclear and Myotubular Myopathies and Latest Treatment Advances. Int J Mol Sci. 2021; 22(21). PMC: 8583656. DOI: 10.3390/ijms222111377. View

Misaka T, Yoshihisa A, Takeishi Y . Titin in muscular dystrophy and cardiomyopathy: Urinary titin as a novel marker. Clin Chim Acta. 2019; 495:123-128. DOI: 10.1016/j.cca.2019.04.005. View

Koga H, Miyako K, Suga N, Hidaka T, Takahashi N . Predisposition to subdural hemorrhage in X-linked myotubular myopathy. Pediatr Neurol. 2012; 46(5):332-4. DOI: 10.1016/j.pediatrneurol.2012.02.026. View

Balhoff J, Carbon S, Ebert D, Gaudet P, Harris N, Mi H . The Gene Ontology knowledgebase in 2023. Genetics. 2023; 224(1). PMC: 10158837. DOI: 10.1093/genetics/iyad031. View

10.

Wenzel K, Zabojszcza J, Carl M, Taubert S, Lass A, Harris C . Increased susceptibility to complement attack due to down-regulation of decay-accelerating factor/CD55 in dysferlin-deficient muscular dystrophy. J Immunol. 2005; 175(9):6219-25. DOI: 10.4049/jimmunol.175.9.6219. View

11.

Morales L, Gambhir Y, Bennett J, Stedman H . Broader Implications of Progressive Liver Dysfunction and Lethal Sepsis in Two Boys following Systemic High-Dose AAV. Mol Ther. 2020; 28(8):1753-1755. PMC: 7363592. DOI: 10.1016/j.ymthe.2020.07.009. View

12.

Esposito L, Melov S, Panov A, Cottrell B, Wallace D . Mitochondrial disease in mouse results in increased oxidative stress. Proc Natl Acad Sci U S A. 1999; 96(9):4820-5. PMC: 21775. DOI: 10.1073/pnas.96.9.4820. View

13.

Anders S, Pyl P, Huber W . HTSeq--a Python framework to work with high-throughput sequencing data. Bioinformatics. 2014; 31(2):166-9. PMC: 4287950. DOI: 10.1093/bioinformatics/btu638. View

14.

Ketel K, Krauss M, Nicot A, Puchkov D, Wieffer M, Muller R . A phosphoinositide conversion mechanism for exit from endosomes. Nature. 2016; 529(7586):408-12. DOI: 10.1038/nature16516. View

15.

Djeddi S, Reiss D, Menuet A, Freismuth S, de Carvalho Neves J, Djerroud S . Multi-omics comparisons of different forms of centronuclear myopathies and the effects of several therapeutic strategies. Mol Ther. 2021; 29(8):2514-2534. PMC: 8353243. DOI: 10.1016/j.ymthe.2021.04.033. View

16.

Cowling B, Toussaint A, Amoasii L, Koebel P, Ferry A, Davignon L . Increased expression of wild-type or a centronuclear myopathy mutant of dynamin 2 in skeletal muscle of adult mice leads to structural defects and muscle weakness. Am J Pathol. 2011; 178(5):2224-35. PMC: 3081151. DOI: 10.1016/j.ajpath.2011.01.054. View

17.

Micallef L, Rodgers P . eulerAPE: drawing area-proportional 3-Venn diagrams using ellipses. PLoS One. 2014; 9(7):e101717. PMC: 4102485. DOI: 10.1371/journal.pone.0101717. View

18.

Molera C, Sarishvili T, Nascimento A, Rtskhiladze I, Munoz Bartolo G, Fernandez Cebrian S . Intrahepatic Cholestasis Is a Clinically Significant Feature Associated with Natural History of X-Linked Myotubular Myopathy (XLMTM): A Case Series and Biopsy Report. J Neuromuscul Dis. 2021; 9(1):73-82. PMC: 8842755. DOI: 10.3233/JND-210712. View

19.

Wu T, Hu E, Xu S, Chen M, Guo P, Dai Z . clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation (Camb). 2021; 2(3):100141. PMC: 8454663. DOI: 10.1016/j.xinn.2021.100141. View

20.

Childers M, Joubert R, Poulard K, Moal C, Grange R, Doering J . Gene therapy prolongs survival and restores function in murine and canine models of myotubular myopathy. Sci Transl Med. 2014; 6(220):220ra10. PMC: 4105197. DOI: 10.1126/scitranslmed.3007523. View