Up-regulating autophagy by targeting the mTOR-4EBP1 pathway: a possible mechanism for improving cardiac function in mice with experimental dilated cardiomyopathy

Jin, Bo; H, Shi; Zhu, Jun; Wu, Bangwei; Geshang, Quzhen

doi:10.1186/s12872-020-01365-9

Cited by 7 publications

(4 citation statements)

References 26 publications

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“…50 Recent studies in clinical and experimental models of DCM have implicated mTOR hyperactivation as a major cause of DCM. 51,52 In line with this, inhibition of mTOR by rapamycin has been demonstrated to successfully improve cardiac function in animal models of DCM. [53][54][55] Of note, not all identified RRAGD mutations overactivated mTORC1 signaling equally.…”

Section: Discussionmentioning

confidence: 83%

mTOR-Activating Mutations in RRAGD Are Causative for Kidney Tubulopathy and Cardiomyopathy

Schlingmann

Jouret

Shen

et al. 2021

JASN

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Background Over the last decade, advances in genetic techniques have resulted in the identification of rare hereditary disorders of renal magnesium and salt handling. Nevertheless, approximately 20% of all tubulopathy patients lack a genetic diagnosis. Methods We performed whole-exome and genome sequencings of a patient cohort with a novel inherited salt-losing tubulopathy, hypomagnesemia, and dilated cardiomyopathy. We also conducted subsequent functional analyses in vitro of identified variants of RRAGD, a gene that encodes a small Rag guanosine triphosphatase (GTPase). Results In eight children from unrelated families with a tubulopathy characterized by hypomagnesemia, hypokalemia, salt wasting, and nephrocalcinosis, we identified heterozygous missense variants in RRAGD that mostly occurred de novo. Six of these patients also had dilated cardiomyopathy and three underwent heart transplantation. We identified a heterozygous variant in RRAGD that segregated with the phenotype in eight members of a large family with similar kidney manifestations. The GTPase RagD encoded by RRAGD plays a role in mediating amino acid signaling to the mechanistic target of rapamycin complex 1 (mTORC1). RagD expression along the mammalian nephron included the thick ascending limb and the distal convoluted tubule. The identified RRAGD variants were shown to induce a constitutive activation of mTOR signaling in vitro. Conclusions Our findings establish a novel disease, which we call autosomal dominant kidney hypomagnesemia (ADKH-RRAGD), that combines an electrolyte-losing tubulopathy and dilated cardiomyopathy. The condition is caused by variants in the RRAGD gene, which encodes Rag GTPase D; these variants lead to an activation of mTOR signaling, suggesting a critical role of Rag GTPase D for renal electrolyte handling and cardiac function.

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Section: Discussionmentioning

confidence: 83%

mTOR-Activating Mutations in RRAGD Are Causative for Kidney Tubulopathy and Cardiomyopathy

Schlingmann

Jouret

Shen

et al. 2021

JASN

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“…mTOR–4EBP pathway is essential for the maintenance of cardiac structure and function in the postnatal period and adulthood 26 , 27 , 32 . In our study, decreased phosphorylation of mTOR (Ser2448) and 4EBP1 (Thr37/46) were observed in both LV and RV of CS- Dsg2 −/− mice ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Reactivation of PPARα alleviates myocardial lipid accumulation and cardiac dysfunction by improving fatty acid β-oxidation in Dsg2-deficient arrhythmogenic cardiomyopathy

Lin

Liu

Huang

et al. 2023

Acta Pharmaceutica Sinica B

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“…(34) Recent studies in clinical and experimental models of DCM have implicated mTOR hyperactivation as a major cause of DCM. (35, 36) In line, inhibition of mTOR by rapamycin has been demonstrated to successfully improve cardiac function in animal models of DCM. (37-39) Of note, not all identified RRAGD mutations overactivated mTORC1 signaling equally.…”

Section: Discussionmentioning

confidence: 98%

mTOR-activating mutations inRRAGDcause kidney tubulopathy and cardiomyopathy (KICA) syndrome

Schlingmann¹,

Shen

Baaij

2021

Preprint

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Over the last decaces, advances in genetic techniques have resulted in the identification of rare hereditary disorders of renal magnesium and salt handling. Nevertheless, 20% of all tubulopathy patients remain without genetic diagnosis. Here, we explore a large multicentric patient cohort with a novel inherited salt-losing tubulopathy, hypomagnesemia and dilated cardiomyopathy (DCM). Whole exome and genome sequencings were performed with various subsequent functional analyses of identified RRAGD variants in vitro. In 8 children from unrelated families with a tubulopathy characterized by hypomagnesemia, hypokalemia, salt-wasting, and nephrocalcinosis, we identified heterozygous missense variants in RRAGD that mostly occurred de novo. Six of these patients additionally suffered from DCM requiring heart transplantation in 3 of them. An additional dominant variant in RRAGD was simultaneously identified in eight members of a large family with a similar renal phenotype. RRAGD encodes GTPase RagD mediating amino acid signaling to the mechanistic target of rapamycin complex 1 (mTORC1). RagD expression along the mammalian nephron include the thick ascending limb and the distal convoluted tubule. The identified RRAGD variants were shown to induce a constitutive activation of mTOR signaling in vitro. Our findings establish a novel disease phenotype combining kidney tubulopathy and cardiomyopathy (KICA) caused by an activation of mTOR signaling suggesting a critical role of Rag GTPase D for renal electrolyte handling and cardiac function.

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Up-regulating autophagy by targeting the mTOR-4EBP1 pathway: a possible mechanism for improving cardiac function in mice with experimental dilated cardiomyopathy

Cited by 7 publications

References 26 publications

mTOR-Activating Mutations in RRAGD Are Causative for Kidney Tubulopathy and Cardiomyopathy

mTOR-Activating Mutations in RRAGD Are Causative for Kidney Tubulopathy and Cardiomyopathy

Reactivation of PPARα alleviates myocardial lipid accumulation and cardiac dysfunction by improving fatty acid β-oxidation in Dsg2-deficient arrhythmogenic cardiomyopathy

mTOR-activating mutations inRRAGDcause kidney tubulopathy and cardiomyopathy (KICA) syndrome

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