Mammalian γ2 AMPK regulates intrinsic heart rate

Yavari, Arash; Bellahcene, Mohamed; Bucchi, Annalisa; Sirenko, Syevda; Pintér, Katalin; Herring, Neil; Jung, Julia Jeannine; Tarasov, Kirill V.; Sharpe, Emily J.; Wolfien, Markus; Czibik, Gabor; Steeples, Violetta; Ghaffari, Sahar; Nguyen, Chinh Duc; Stockenhuber, Alexander; Clair, Joshua R. St.; Rimmbach, Christian; Okamoto, Y.; Yang, Dongmei; Wang, Mingyi; Ziman, Bruce D.; Moen, Jack M.; Riordon, Daniel R.; Ramirez, Christopher; Paina, Manuel; Lee, Joonho; Zhang, Jing; Ahmet, Ismayil; Matt, Michael G.; Tarasova, Yelena S.; Baban, Dilair; Sahgal, Natasha; Lockstone, Helen; Puliyadi, Rathi; Bono, Joseph de; Siggs, Owen M.; Gomes, John; Muskett, H; Maguire, Mahon L.; Beglov, Youlia; Kelly, Matthew; Santos, Pedro Paulo N; Bright, Nicola J.; Woods, Angela; Gehmlich, Katja; Isackson, Henrik; Douglas, Gillian; Ferguson, David J. P.; Schneider, Jürgen; Tinker, Andrew; Wolkenhauer, Olaf; Channon, Keith M.; Cornall, Richard J.; Sternick, Eduardo Back; Paterson, David J.; Redwood, Charles; Carling, David; Proenza, Catherine; Dávid, Róbert; Baruscotti, Mirko; DiFrancesco, Dario; Lakatta, Edward G.; Watkins, Hugh; Ashrafian, Houman

doi:10.1038/s41467-017-01342-5

Cited by 47 publications

(48 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A vital prerequisite for life is a balanced energy balance that is disturbed in patients with anorexia nervosa. In mammals, for which heart rate is a key determinant of cardiac energy demand, AMPK functions in an organspecific manner seems to maintain cardiac energy homeostasis and determines cardiac physiological adaptation to caloric intake by modulating intrinsic sinoatrial cell behavior probably via HCN4 protein expression [19]. Our data clearly support the dominance of the intrinsic heart regulation via sinus node regulation over autonomic regulation in anorexia nervosa.…”

Section: Biology Of the Interplay Between Caloric Intake And Heart Rasupporting

confidence: 67%

Heart rate regulation in patients with anorexia nervosa

Baumann¹,

Buchhorn²,

Willaschek³

2019

View full text Add to dashboard Cite

Background and Aims: To examine the effects of starvation and nutritional refeeding on heart rate variability (HRV) and heart rate in adolescents with Anorexia Nervosa. Method: For this publication we illustrate 3 precedential cases to explain our model of heart rate regulation in patients with Anorexia Nervosa. Results: The linear relationship between the range of normal RR-intervals, global heart rate variability (SDNN) and mean heart rate is explainable by the slope of the diastolic depolarization of sinus node cells, regulated by the funny channels. We demonstrate the relationship between caloric intake, heart rate and heart rate variability which is better explained by the regulation of the funny channels than by the autonomic nervous system. However, the impaired heart rate regulation induces dysautonomia, demonstrated in two patients who develop postural orthostatic tachycardia syndrome (POTS). Based upon this model we explain the therapeutics effects of beta blockers, midodrine and ivabradine in these patients. Discussion: Our model of heart rate regulation in patients with Anorexia Nervosa explains dysautonomia in these patients and the effect of refeeding on heart rate regulation. Treatment of the impaired heart rate regulation in these patients with beta blockers, midodrine and ivrabradine can improve the oftenunsatisfactory therapy results.

show abstract

Section: Biology Of the Interplay Between Caloric Intake And Heart Rasupporting

confidence: 67%

Heart rate regulation in patients with anorexia nervosa

Baumann¹,

Buchhorn²,

Willaschek³

2019

View full text Add to dashboard Cite

show abstract

“…These had lower LVSP, dP/dt max , dP/dt min , and heart rate at rest and during exercise, yet exercise performance was unaffected, suggesting positive adaptations akin to those seen with endurance training (Adams et al, 1995). These include AMPK activation in sinoatrial cells, which has been shown to lower resting heart rate in order to reduce cardiac energy demand (Yavari et al, 2017). However, our phenotype may have been even more robust if we had studied mice older than 18 months.…”

Section: A a T T T T T T T T T T T T To O O O O O O O O O O O O O O Omentioning

confidence: 88%

Age-Dependent Decline in Cardiac Function in Guanidinoacetate-N-Methyltransferase Knockout Mice

et al. 2020

View full text Add to dashboard Cite

Aim: Guanidinoacetate N-methyltransferase (GAMT) is the second essential enzyme in creatine (Cr) biosynthesis. Short-term Cr deficiency is metabolically well tolerated as GAMT −/− mice exhibit normal exercise capacity and response to ischemic heart failure. However, we hypothesized long-term consequences of Cr deficiency and/or accumulation of the Cr precursor guanidinoacetate (GA).Methods: Cardiac function and metabolic profile were studied in GAMT −/− mice >1 year.Results: In vivo LV catheterization revealed lower heart rate and developed pressure in aging GAMT −/− but normal lung weight and survival versus age-matched controls. Electron microscopy indicated reduced mitochondrial volume density in GAMT −/− hearts (P < 0.001), corroborated by lower mtDNA copy number (P < 0.004), and citrate synthase activity (P < 0.05), however, without impaired mitochondrial respiration. Furthermore, myocardial energy stores and key ATP homeostatic enzymes were barely altered, while pathology was unrelated to oxidative stress since superoxide production and protein carbonylation were unaffected. Gene expression of PGC-1α was 2.5-fold higher in GAMT −/− hearts while downstream genes were not activated, implicating a dysfunction in mitochondrial biogenesis signaling. This was normalized by 10 days of dietary Cr supplementation, as were all in vivo functional parameters, however, it was not possible to differentiate whether relief from Cr deficiency or GA toxicity was causative.Conclusion: Long-term Cr deficiency in GAMT −/− mice reduces mitochondrial volume without affecting respiratory function, most likely due to impaired biogenesis. This is associated with hemodynamic changes without evidence of heart failure, which may represent an acceptable functional compromise in return for reduced energy demand in aging mice.

show abstract

“…Loss of cardiac AMPK reduces systolic and diastolic function, an effect that results in ventricular shortening in the absence of changes in fatty acid or glucose metabolism or cardiac hypertrophy 95,263 . However, hypertrophy is also observed with chronic genetic and pharmacological activation of AMPK, effects that, in contrast to Wolff-Parkinson-White syndrome, have been associated with increased stroke volume 26,195,264 and subsequent reductions in heart rate 265 , suggesting that activation of cardiac AMPK may be potentially beneficial in people with heart failure. However, the pathways controlling cardiac hypertrophy are complex, and under some conditions, the activation of AMPK has been shown to be protective against cardiac hypertrophy 266 .…”

Section: ) (Table 1)mentioning

confidence: 99%

AMP-activated protein kinase: the current landscape for drug development

Steinberg

Carling

2019

Nat Rev Drug Discov

Self Cite

445

405

View full text Add to dashboard Cite

Since the discovery of AMP-activated protein kinase (AMPK) as a central regulator of energy homeostasis, many exciting insights into its structure, regulation and physiological roles have been revealed. While exercise, caloric restriction, metformin and many natural products increase AMPK activity and exert a multitude of health benefits, developing direct activators of AMPK to elucidate the role of AMPK in these beneficial effects has been challenging. However, in recent years, direct AMPK activators have been identified and tested in preclinical models, and a small number have entered clinical trials. Despite these advances, which disease(s) represent the best indications for therapeutic AMPK activation and the long-term safety of such approaches remain to be established. Commented [WS2]: Au: "The optimal consensus motif of AMPK substrates has been established (BOX 3)" OK?

show abstract

Mammalian γ2 AMPK regulates intrinsic heart rate

Cited by 47 publications

References 76 publications

Heart rate regulation in patients with anorexia nervosa

Heart rate regulation in patients with anorexia nervosa

Age-Dependent Decline in Cardiac Function in Guanidinoacetate-N-Methyltransferase Knockout Mice

AMP-activated protein kinase: the current landscape for drug development

Contact Info

Product

Resources

About