Role of mTOR in the regulation of skeletal muscle metabolism

Golberg, Natalia D.; Druzhevskaya, Anastasiya M.; Рогозкин, В. А.; Ahmetov, Ildus I.

doi:10.1134/s0362119714040070

Cited by 6 publications

(3 citation statements)

References 56 publications

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“…Since mTOR is located downstream of AMPK and mTOR has been well reported to regulate muscle growth and metabolism 42 , 43 as well as the eIF4EBP3L as a gatekeeper of mTOR in muscle growth 44 , we next examined the effect of mTOR pathway by measuring the levels of mTOR and eif4ebp3l in the LMNA mutant transgenic fish with or without drug treatment. Intriguingly, similar to the results in ampk (Fig.…”

Section: Resultsmentioning

confidence: 99%

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

Pan,

Wang,

Hsiao

et al. 2024

Sci Rep

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Lamin A/C gene (LMNA) mutations contribute to severe striated muscle laminopathies, affecting cardiac and skeletal muscles, with limited treatment options. In this study, we delve into the investigations of five distinct LMNA mutations, including three novel variants and two pathogenic variants identified in patients with muscular laminopathy. Our approach employs zebrafish models to comprehensively study these variants. Transgenic zebrafish expressing wild-type LMNA and each mutation undergo extensive morphological profiling, swimming behavior assessments, muscle endurance evaluations, heartbeat measurement, and histopathological analysis of skeletal muscles. Additionally, these models serve as platform for focused drug screening. We explore the transcriptomic landscape through qPCR and RNAseq to unveil altered gene expression profiles in muscle tissues. Larvae of LMNA(L35P), LMNA(E358K), and LMNA(R453W) transgenic fish exhibit reduced swim speed compared to LMNA(WT) measured by DanioVision. All LMNA transgenic adult fish exhibit reduced swim speed compared to LMNA(WT) in T-maze. Moreover, all LMNA transgenic adult fish, except LMNA(E358K), display weaker muscle endurance than LMNA(WT) measured by swimming tunnel. Histochemical staining reveals decreased fiber size in all LMNA mutations transgenic fish, excluding LMNA(WT) fish. Interestingly, LMNA(A539V) and LMNA(E358K) exhibited elevated heartbeats. We recognize potential limitations with transgene overexpression and conducted association calculations to explore its effects on zebrafish phenotypes. Our results suggest lamin A/C overexpression may not directly impact mutant phenotypes, such as impaired swim speed, increased heart rates, or decreased muscle fiber diameter. Utilizing LMNA zebrafish models for drug screening, we identify 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 swim 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 faithfully mimic clinical manifestations of muscular laminopathies, including dysmorphism, early mortality, decreased fiber size, and muscle dysfunction in zebrafish. Furthermore, our drug screening results suggest l-carnitine and creatine treatments as potential rescuers of muscle endurance in LMNA(L35P) and LMNA(R453W) zebrafish models. Our study offers valuable insights into the future development of potential treatments for LMNA-related muscular laminopathy.

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Section: Resultsmentioning

confidence: 99%

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

Pan,

Wang,

Hsiao

et al. 2024

Sci Rep

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“…The expression of Mammalian Target of Rapamycin (mTOR) mRNA was higher (p \ 0.01) in glutamine-treated group than in non-treated group in day 6. Consistently, cellular protein concentration was higher (p \ 0.01) in glutamine-treated group than in non-treated group in day 6. mTOR known for master regulator of cellular protein metabolism, is regulated by leucine primarily and critical for protein synthesis in muscle [18,19]. During myogenesis especially in late stage of differentiation, differentiated primary myotubes go on secondary myotube maturation stage, when cellular protein synthesis and fusions are occurred dramatically in muscle cells via mTOR-pathway [20].…”

Section: Resultsmentioning

confidence: 99%

Effect of glutamine on heat-shock protein beta 1 (HSPB1) expression during myogenic differentiation in bovine embryonic fibroblast cells

Kim

Lee

et al. 2018

Food Sci Biotechnol

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The objective of this study was to examine the effects of glutamine on heat-shock protein beta 1 () expression in bovine embryonic fibroblast cells during myogenesis. First, to elucidate the role of glutamine on expression during myogenesis, we treated with glutamine in myogenic lineage determinant (MyoD) over-expressed bovine embryonic fibroblast cells (BEFS-MyoD cells). Second, knockdown of using small interference RNA was performed to evaluate whether muscle development by glutamine is dependent on in BEFS-MyoD cells. As a result, glutamine promoted the mRNA level of, ,, and mTOR as well as myotube formation, and protein synthesis ( < 0.05). The inhibition of expression during myogenesis has shown to repress the expression of myogenic marker genes (MyoD,, ) ( < 0.01), formation of myotubes and protein synthesis ( < 0.05). According to the results, it is concluded that glutamine regulates expression during myogenesis.

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“…Since mTOR is loacted downstream of AMPK and mTOR has been well reported to regulate muscle growth and metabolism 37,38 as well as the eIF4EBP3L as a gatekeeper of mTOR in muscle growth 39 , we next examined th effect of mTOR pathway by measuring the levels of mTOR and eif4ebp3l in the LMNA mutant transgenic sh with or without drug treatment. Intriguingly, similar to the results in ampk (Figure 7B, B'), the levels of mTOR expression were also signi cantly increased in the creatine treated LMNA(R453W) sh(Figure 7E, E'), implicating the possibility of AMPK/mTOR axis in improving muscle endurance in LMNA(R453W) sh by creatine treatment.…”

Section: Impaired Swimming Speed In Adult Transgenic Sh With Lmna Mut...mentioning

confidence: 99%

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

Yuh,

Pan,

Wang

et al. 2023

Preprint

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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.

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Role of mTOR in the regulation of skeletal muscle metabolism

Cited by 6 publications

References 56 publications

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

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

Effect of glutamine on heat-shock protein beta 1 (HSPB1) expression during myogenic differentiation in bovine embryonic fibroblast cells

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

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