Abstract
Striated muscle laminopathies are cardiac and skeletal muscle conditions caused by mutations in the lamin A/C gene (LMNA). LMNA codes for the A-type lamins, which are nuclear intermediate filaments that maintain the nuclear structure and nuclear processes such as gene expression. Protein kinase C alpha (PKC-α) interacts with lamin A/C and with several lamin A/C partners involved in striated muscle laminopathies. To determine PKC-α’s involvement in muscular laminopathies, PKC-α’s localization, activation, and interactions with the A-type lamins were examined in various cell types expressing pathogenic lamin A/C mutations. The results showed aberrant nuclear PKC-α cellular distribution in mutant cells compared to WT. PKC-α activation (phos-PKC-α) was decreased or unchanged in the studied cells expressing LMNA mutations, and the activation of its downstream targets, ERK 1/2, paralleled PKC-α activation alteration. Furthermore, the phos-PKC-α-lamin A/C proximity was altered. Overall, the data showed that PKC-α localization, activation, and proximity with lamin A/C were affected by certain pathogenic LMNA mutations, suggesting PKC-α involvement in striated muscle laminopathies.
Highlights
Lamins A and C are A-type lamins coded by the lamin A/C (LMNA) gene
Lmna H222P mouse model and in patients with dilated cardiomyopathy (DCM) caused by lamin A/C mutations, show that members of the MAP kinase (MAPK) signaling pathway, ERK 1/2 and several of its downstream targets, are highly expressed/active [49,50,51]
Striated muscle laminopathies affect the majority of individuals carrying pathogenic lamin A/C
Summary
Lamins A and C are A-type lamins coded by the lamin A/C (LMNA) gene. They are nuclear intermediate filaments important for structural support and maintenance of various nuclear processes, such as gene expression [1]. Emery-Dreifuss muscular dystrophy (EDMD) and LMNA-related congenital muscular dystrophy (L-CMD) are skeletal muscle conditions caused by lamin A/C mutations [9,10,11] Both dystrophies have childhood onset and overlapping clinical presentations [12]. Lmna H222P mouse model and in patients with DCM caused by lamin A/C mutations, show that members of the MAP kinase (MAPK) signaling pathway, ERK 1/2 and several of its downstream targets, are highly expressed/active [49,50,51]. A/C proximity in the presence of pathogenic lamin A/C mutations using cardiac and skeletal myoblast cell lines; striated muscle laminopathy mouse model myoblasts; and fibroblasts and myoblasts from two L-CMD patients carrying distinct mutations. PKC-α and ERK 1/2 activations were decreased or unchanged in patient cells and in skeletal myoblasts from two different mouse models of striated muscle laminopathies. The results demonstrate for the first time the involvement of PKC-α in cardiac and muscular laminopathies
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