Point mutated caveolin-3 form (P104L) impairs myoblast differentiation via Akt and p38 signalling reduction, leading to an immature cell signature

Abstract

Unbalanced levels of caveolin-3 (Cav3) are involved in muscular disorders. In the present study we show that differentiation of immortalized myoblasts is affected by either lack or overexpression of Cav3. Nevertheless, depletion of Cav3 induced by delivery of the dominant-negative Cav3 (P104L) form elicited a more severe phenotype, characterized by the simultaneous attenuation of the Akt and p38 signalling networks, leading to an immature cell and molecular signature. Accordingly, differentiation of myoblasts harbouring Cav3 (P104L) was improved by countering the reduced Akt and p38 signalling network via administration of IGF-1 or trichostatin A. Furthermore, loss of Cav3 correlated with a deregulation of the TGF-β-induced Smad2 and Erk1/2 pathways, confirming that Cav3 controls TGF-β signalling at the plasma membrane. Overall, these data suggest that loss of Cav3, primarily causing attenuation of both Akt and p38 pathways, contributes to impair myoblast fusion.

MURC/cavin-4 Is Co-Expressed with Caveolin-3 in Rhabdomyosarcoma Tumors and Its Silencing Prevents Myogenic Differentiation in the Human Embryonal RD Cell Line

“…Cav-3 is a membrane scaffolding protein [61–63] that interacting at the sarcolemma with a number of signalling proteins, such as nitric oxide synthase [64, 65], TGF-β (transforming growth factor-beta) receptors [66, 67] and dysferlin [68, 69], is involved in the regulation of many processes, including skeletal muscle differentiation and regeneration. Mutated Cav-3 forms affect the survival and differentiation of myoblasts [70, 71] and are involved in the onset of cardiac and neuromuscular disorders [72–75], such as the Limb Girdle Muscular Dystrophy 1-C [64, 65, 76, 77]. Furthermore, Cav-3 deficient muscles from dystrophic patients display a loss of MURC/cavin-4 [52], suggesting that MURC/cavin-4 and Cav-3 may together cooperate for proper functioning of skeletal muscle tissue.…”

An inhibitor of transforming growth factor beta type I receptor ameliorates muscle atrophy in a mouse model of caveolin 3-deficient muscular dystrophy

“…29,49 Caveolin 3-deficient myoblasts formed thin myotubes upon activation of the TGF-b effector, Smad2. 29 Activated Smad2 was also observed in skeletal muscle from patients with muscular dystrophy with generalized lipodystrophy caused by deficiency of cavin, an assembly molecule for caveolin 3.…”

“…29,49 Caveolin 3-deficient myoblasts formed thin myotubes upon activation of the TGF-b effector, Smad2. 29 Activated Smad2 was also observed in skeletal muscle from patients with muscular dystrophy with generalized lipodystrophy caused by deficiency of cavin, an assembly molecule for caveolin 3. 49 To confirm the novel concept of the caveolin 3-TGF-b-p21 axis in the pathobiology of muscle atrophy, further characterization of both satellite cells and myoblasts will be required in skeletal muscle samples from patients with LGMD1C and cavin 1 deficiency.…”

“…5 Moreover, other groups have reported that expression of a CAV3 antisense RNA, or a Pro104Leu dominant-negative mutant CAV3 cDNA suppressed the differentiation of C2C12 myoblasts into myotubes under low-serum conditions. 28,29 We thus expressed the Pro104Leu dominant-negative mutant CAV3 cDNA in C2C12 cells using the above retroviral system, to explore the molecular significance of caveolin 3 and TGF-b signals in myoblast differentiation. Similarly to the results of the TGF-b expression, myotube formation was impaired in C2C12 myoblasts overexpressing Pro104Leu mutant caveolin 3, compared with controls (Figure 3a-c).…”

Recent Progress in the Topology, Structure, and Oligomerization of Caveolin: A Building Block of Caveolae

“…Caveolin-3 has been linked to many muscular diseases such as heart disease and muscular dystrophy (Horikawa et al, 2008;Weiss et al, 2008). P104 in caveolin-3 which is analogous to P132 in caveolin-1 is also implicated in increased disease states and misregulation of the protein (Ohsawa et al, 2004;Stoppani et al, 2011).…”