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Abstract
Several human diseases are associated with a lack of caveolae. Yet, the functions of caveolae and the molecular mechanisms critical for shaping them still are debated. We show that muscle cells of syndapin III KO mice show severe reductions of caveolae reminiscent of human caveolinopathies. Yet, different from other mouse models, the levels of the plasma membrane-associated caveolar coat proteins caveolin3 and cavin1 were both not reduced upon syndapin III KO. This allowed for dissecting bona fide caveolar functions from those supported by mere caveolin presence and also demonstrated that neither caveolin3 nor caveolin3 and cavin1 are sufficient to form caveolae. The membrane-shaping protein syndapin III is crucial for caveolar invagination and KO rendered the cells sensitive to membrane tensions. Consistent with this physiological role of caveolae in counterpoising membrane tensions, syndapin III KO skeletal muscles showed pathological parameters upon physical exercise that are also found in CAVEOLIN3 mutation-associated muscle diseases.
Highlights
Caveolae - uniform plasma membrane invaginations with ~70 nm diameter - were first described more than 60 years ago (Yamada, 1955)
Toward addressing the role of caveolar invaginations in the various diseases associated with CAV3 mutations, we studied the muscle-enriched member of the syndapin family (Kessels and Qualmann, 2004; Qualmann et al, 2011), syndapin III (Figure 1a), by generating syndapin III KO mice
Model systems with caveolin-deficiency are unable to distinguish between these possibilities, as they lack both invaginated caveolae and caveolins (Hansen and Nichols, 2010; Nassoy and Lamaze, 2012; Parton and del Pozo, 2013; Shvets et al, 2014; Cheng and Nichols, 2016)
Summary
Caveolae - uniform plasma membrane invaginations with ~70 nm diameter - were first described more than 60 years ago (Yamada, 1955). Their functions are still matter of debate. CAV3 mutations manifest in several human diseases, for example limb girdle muscular dystrophy (LGMD), rippling muscle disease (RMD), hyperCK(creatine kinase)emia, distal myopathy, hypertrophic cardiomyopathy, arrhythmogenic-long-QT syndrome and sudden-infant-death syndrome. Most patients with CAV3 mutations are heterozygous and the pathophysiology seems to be caused by the mutated protein acting dominant-negatively on WT-cav via self-association (Gazzerro et al, 2010). Overexpression of dominant-negative mutants in mice caused symptoms resembling hypertrophic cardiomyopathy (Ohsawa et al, 2004)
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