Dystrophy-associated caveolin-3 mutations reveal that caveolae couple IL6/STAT3 signaling with mechanosensing in human muscle cells.
Melissa DewulfDarius Vasco KösterBidisha SinhaChristine Viaris de LesegnoValérie ChambonAnne BigotMona BensalahElisa NegroniNicolas TardifJoanna PodkalickaLudger JohannesPierre NassoyGillian Butler-BrowneChristophe LamazeCedric M BlouinPublished in: Nature communications (2019)
Caveolin-3 is the major structural protein of caveolae in muscle. Mutations in the CAV3 gene cause different types of myopathies with altered membrane integrity and repair, expression of muscle proteins, and regulation of signaling pathways. We show here that myotubes from patients bearing the CAV3 P28L and R26Q mutations present a dramatic decrease of caveolae at the plasma membrane, resulting in abnormal response to mechanical stress. Mutant myotubes are unable to buffer the increase in membrane tension induced by mechanical stress. This results in impaired regulation of the IL6/STAT3 signaling pathway leading to its constitutive hyperactivation and increased expression of muscle genes. These defects are fully reversed by reassembling functional caveolae through expression of caveolin-3. Our study reveals that under mechanical stress the regulation of mechanoprotection by caveolae is directly coupled with the regulation of IL6/STAT3 signaling in muscle cells and that this regulation is absent in Cav3-associated dystrophic patients.
Keyphrases
- signaling pathway
- induced apoptosis
- end stage renal disease
- skeletal muscle
- poor prognosis
- ejection fraction
- newly diagnosed
- chronic kidney disease
- genome wide
- endothelial cells
- peritoneal dialysis
- cell cycle arrest
- gene expression
- cell death
- endoplasmic reticulum stress
- long non coding rna
- single cell
- amino acid
- patient reported
- transcription factor