Translational regulation by miR-301b upregulates AMP deaminase in diabetic hearts

Tatekoshi, Yuki; Tanno, Masaya; Kouzu, Hidemichi; Abe, Koki; Miki, Takayuki; Kuno, Atsushi; Yano, Toshiyuki; Ishikawa, Satoko; Ohwada, Wataru; Sato, Tatsuya; Niinuma, Takeshi; Suzuki, Hiromu; Miura, Tetsuji

doi:10.1016/j.yjmcc.2018.05.003

Cited by 15 publications

(24 citation statements)

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“…Interestingly, we previously showed that hypertrophy is not observed in pediatric DCM hearts ( 13 ). In addition, increased expression of miR-301b has been reported in non-valvular atrial fibrillation patients compared to healthy controls ( 36 ), whereas inhibition of miR-301b expression in neonatal rats has been implicated in reduced ATP production and contractile dysfunction ( 37 ).…”

Section: Discussionmentioning

confidence: 99%

Integrated analysis of miRNA–mRNA interaction in pediatric dilated cardiomyopathy

Hailu

Karimpour-Fard²,

Toni

et al. 2021

Pediatr Res

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Background microRNAs (miRNAs) are short single stranded nucleotides that can regulate gene expression. Although we previously evaluated expression of miRNAs in pediatric dilated cardiomyopathy (DCM) by miRNA array, pathway prediction based on changes in mRNA expression has not been previous analyzed in this population. The current study aimed to determine regulation of miRNA expression by miRNA-Seq and, through mRNA-Seq, analyze their putative target genes and altered pathways in pediatric DCM hearts. Methods miRNA expression was determined by miRNA-Seq [n=10 non-failing (NF), n=20 DCM]. Expression of a subset of miRNAs was evaluated in adult DCM patients (n=11 NF, n=13 DCM). miRNA-mRNA prediction analysis was performed using mRNA-Seq data (n=7 NF, n=7 DCM) from matched samples. Results Expression of 393 miRNAs was significantly different (p<0.05) in pediatric DCM patients compared to NF controls. TargetScan-based miRNA-mRNA analysis revealed 808 significantly inversely expressed genes. Functional analysis suggests up-regulated pathways related regulation of stem cell differentiation and cardiac muscle contraction, and down-regulated pathways related to regulation of protein phosphorylation, signal transduction and cell communication. Conclusion Our results demonstrated a unique age-dependent regulation of miRNAs and their putative target genes which may contribute to distinctive phenotypic characteristics of DCM in children.

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Section: Discussionmentioning

confidence: 99%

Integrated analysis of miRNA–mRNA interaction in pediatric dilated cardiomyopathy

Hailu

Karimpour-Fard²,

Toni

et al. 2021

Pediatr Res

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“…During hyperthermia, glucose metabolism is required to maintain the cellular ATP content, and energy substrates are crucial for the recovery of injured cells. Tatekoshi et al () reported that miR‐301b upregulates AMP deaminase in the heart in a rat model of type 2 diabetes mellitus. We found that hyperthermia enhanced miR‐8‐3p expression to decrease ATP concentrations, and increased AMP concentrations in SCs.…”

Section: Discussionmentioning

confidence: 99%

MiR‐8‐3p regulates hyperthermia‐induced lactate secretion by targeting PPP2R5B in boar Sertoli cells

Deng

Tian

et al. 2019

Molecular Reproduction Devel

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Lactate produced by glycolysis in Sertoli cells (SCs) is the main energy substrate for developing germ cells and plays a vital role in spermatogenesis. MicroRNAs (miRNAs) function as posttranscriptional regulators of gene expression in biological processes. We have previously shown that hyperthermia (43°C, 30 min) promotes lactate secretion by inhibiting phosphorylation of adenosine monophosphate‐activated protein kinase (AMPK) in cultured immature boar SCs. However, it is unclear whether miRNAs are involved in AMPK‐modulated glycolysis in SCs. In the present study, we identified 349 miRNAs (227 upregulated and 122 downregulated) in hyperthermia‐treated boar SCs by next‐generation high‐throughput RNA sequencing. MiR‐8‐3p, which was found to be a novel upregulated miRNA in hyperthermia‐treated SCs, suppressed the expression of AMPK upstream genes (protein phosphatase 2 subunit B, PPP2R5B), and further downregulated the expression of p‐AMPK. The miR‐8‐3p mimic upregulated expression of glucose transporter 3, lactate dehydrogenase A and monocarboxylate transporter 1, and increased lactic acid dehydrogenase activity, lactate secretion, and ATP depletion in SCs; the miR‐8‐3p inhibitor had the opposite effects on these parameters. Our findings indicate that miR‐8‐3p acts as a novel regulator of AMPK‐modulated lactate secretion by targeting PPP2R5B in hyperthermic boar SCs.

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“…The cells were used for experiments when they were 70%–90% confluent. Neonatal rat cardiomyocytes (NRCMs) were isolated as previously described (Tatekoshi et al, 2018 ). NRCMs were plated on fibronectin‐coated plates in culture medium; 500 mL of Medium 199 (Gibco 11150‐059) was fortified by the addition of 5 mL of MEM (Gibco 11140‐050), 5 mL l ‐glutamine (200 mM, Gibco 25030‐081), 1.75 g of glucose, 1 mg of vitamin B12, 5 mL of HEPES (1 M, Gibco 15630‐080), 10% FBS and 100 μM bromodeoxyuridine.…”

Section: Methodsmentioning

confidence: 99%

“…Experiments were performed 24–48 h after transfection. FLAG‐AMPD3 or FLAG‐control vector was transfected into H9c2 cells using FuGENE HD (Promega E2311) as previously described (Tatekoshi et al, 2018 ).…”

Section: Methodsmentioning

confidence: 99%

“…We recently reported that upregulated expression of AMP deaminase 3 (AMPD3), a rate‐limiting enzyme in the purine nucleotide cycle, is involved in abnormal cardiac energetics in Otsuka Long‐Evans‐Tokushima fatty (OLETF) rats, models of type 2 diabetes (T2DM) (Igaki et al, 2021 ; Kouzu et al, 2015 ; Tatekoshi et al, 2018 ). The elevated AMPD activity was associated with ATP depletion during acute pressure overload due to excessive degradation of adenine nucleotides (Kouzu et al, 2015 ; Tatekoshi et al, 2018 ), which subsequently facilitated reactive oxygen species production via downstream xanthine oxidoreductase and led to mitochondrial respiratory failure (Igaki et al, 2021 ). Meanwhile, AMPD3 was found to play a central role in coupling fatty acid and BCAA metabolism in skeletal muscle (Hong et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

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Downregulation of extramitochondrial BCKDH and its uncoupling from AMP deaminase in type 2 diabetic OLETF rat hearts

Ogawa

Kouzu

Osanami

et al. 2023

Physiological Reports

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Systemic branched‐chain amino acid (BCAA) metabolism is dysregulated in cardiometabolic diseases. We previously demonstrated that upregulated AMP deaminase 3 (AMPD3) impairs cardiac energetics in a rat model of obese type 2 diabetes, Otsuka Long‐Evans‐Tokushima fatty (OLETF). Here, we hypothesized that the cardiac BCAA levels and the activity of branched‐chain α‐keto acid dehydrogenase (BCKDH), a rate‐limiting enzyme in BCAA metabolism, are altered by type 2 diabetes (T2DM), and that upregulated AMPD3 expression is involved in the alteration. Performing proteomic analysis combined with immunoblotting, we discovered that BCKDH localizes not only to mitochondria but also to the endoplasmic reticulum (ER), where it interacts with AMPD3. Knocking down AMPD3 in neonatal rat cardiomyocytes (NRCMs) increased BCKDH activity, suggesting that AMPD3 negatively regulates BCKDH. Compared with control rats (Long‐Evans Tokushima Otsuka [LETO] rats), OLETF rats exhibited 49% higher cardiac BCAA levels and 49% lower BCKDH activity. In the cardiac ER of the OLETF rats, BCKDH‐E1α subunit expression was downregulated, while AMPD3 expression was upregulated, resulting in an 80% lower AMPD3‐E1α interaction compared to LETO rats. Knocking down E1α expression in NRCMs upregulated AMPD3 expression and recapitulated the imbalanced AMPD3‐BCKDH expressions observed in OLETF rat hearts. E1α knockdown in NRCMs inhibited glucose oxidation in response to insulin, palmitate oxidation, and lipid droplet biogenesis under oleate loading. Collectively, these data revealed previously unrecognized extramitochondrial localization of BCKDH in the heart and its reciprocal regulation with AMPD3 and imbalanced AMPD3‐BCKDH interactions in OLETF. Downregulation of BCKDH in cardiomyocytes induced profound metabolic changes that are observed in OLETF hearts, providing insight into mechanisms contributing to the development of diabetic cardiomyopathy.

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Translational regulation by miR-301b upregulates AMP deaminase in diabetic hearts

Cited by 15 publications

References 50 publications

Integrated analysis of miRNA–mRNA interaction in pediatric dilated cardiomyopathy

Integrated analysis of miRNA–mRNA interaction in pediatric dilated cardiomyopathy

MiR‐8‐3p regulates hyperthermia‐induced lactate secretion by targeting PPP2R5B in boar Sertoli cells

Downregulation of extramitochondrial BCKDH and its uncoupling from AMP deaminase in type 2 diabetic OLETF rat hearts

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