Protein Kinase C Alpha Cellular Distribution, Activity, and Proximity with Lamin A/C in Striated Muscle Laminopathies

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.

A CRISPR/Cas9 zebrafish lamin A/C mutant model of muscular laminopathy

“…Phosphorylation of FLNc by PKC α prevents FLNc cleavage; thus affecting FLNc kinetics and mobility 44 . Our recent work has also suggested PKC α involvement in striated muscle laminopathies in various cellular models 46 . Altogether, these data implicate PKC α in cardiac and skeletal muscle structure and function.…”

“…Aberrant PKC α activation and expression have also been linked to cardiac disease in patients and various animal HF models with pharmacological inhibition or genetic ablation of PKC α leading to improved cardiac function in animal HF models 33,37‐43 . Moreover, our recent work on cellular models suggests PKC α involvement in striated muscle laminopathies 46 . Thus, since cardiac Pkc α expression in zebrafish is unknown, we determined Pkc α expression in zebrafish cardiac tissues by immunostaining cardiac sections of 7 dpf WT and lmna mutant larvae.…”

“…Recent work on cellular models has also implicated Pkc α in striated muscle laminopathies. 46 It would be interesting to investigate Pkc α involvement and function in zebrafish carrying other pathogenic lmna mutations to confirm Pkc α involvement in muscular laminopathies.…”

“…44 Our recent work has also suggested PKC α involvement in striated muscle laminopathies in various cellular models. 46 Altogether, these data implicate PKC α in cardiac and skeletal muscle structure and function.…”

“…33,[37][38][39][40][41][42][43] Moreover, our recent work on cellular models suggests PKC α involvement in striated muscle laminopathies. 46 F I G U R E 2 Cardiac structure and function evaluation and Pkc α immunostaining in WT and mutant lmna zebrafish. A, (i) end systolic and (ii) end diastolic diameters of WT and lmna mutants at 3 and 4 dpf displaying significant difference at 3 dpf between WT and homozygous mutants.…”