Creatine and L-carnitine attenuate muscular laminopathy in the LMNA mutation transgenic zebrafish

Abstract

LMNA gene mutations cause debilitating striated muscle laminopathies, affecting cardiac and skeletal muscles, with limited treatments. This study investigates five LMNA mutations using zebrafish models. Transgenic zebrafish expressing wild-type LMNAand each mutation are extensively profiled for morphology, behavior, and histology, with a focus on skeletal muscles. Drug screening and transcriptomic analysis uncover altered gene expression. Intriguing phenotypes emerge in adult zebrafish with LMNA mutations. LMNA(W520G) variants exhibit a mortality rate within three months. LMNA(A539V) fish exhibit abnormalities in F0 adults and crooked bodies in F1 adults, similar to LMNA(R453W) F1 fish. Larvae of LMNA(L35P), LMNA(E358K), and LMNA(R453W) transgenic fish swim slower than AB(WT) and LMNA(WT) in DanioVision. All LMNA transgenic adult fish, except LMNA(E358K), show reduced swimming speed and muscle endurance compared to AB(WT) in T-maze and swimming tunnel tests. Histochemical staining reveals decreased fiber size in LMNA(L35P), LMNA(E358K), LMNA(R453W), and LMNA(A539V) transgenic fish. Drug screening identifies L-carnitine treatment rescuing muscle endurance in LMNA(L35P) and creatine treatment reversing muscle endurance in LMNA(R453W) zebrafish models. Creatine activates AMPK and mTOR pathways, improving muscle endurance and swimming speed in LMNA(R453W) fish. Transcriptomic profiling reveals upstream regulators and affected genes contributing to motor dysfunction, cardiac anomalies, and ion flux dysregulation in LMNA mutant transgenic fish. These findings mimic clinical manifestations of muscular laminopathies, including dysmorphism, early mortality, decreased fiber size, and muscle dysfunction in zebrafish. Moreover, drug screening suggests L-carnitine and creatine treatments as potential rescuers of muscle endurance in LMNA(L35P) and LMNA(R453W) zebrafish models, offering insights into treating LMNA-related muscular laminopathy.