Moderate heart rate reduction may help cardiac regeneration

aliml

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Highlights​

  • Moderate heart rate reduction promotes cardiomyocytes (cardiac muscle cells) proliferation and heart regeneration
  • Heart rate reduction upregulates metabolic enzymes to induce cardiomyocytes cell cycle re-entry
  • Heart rate reduction activates pentose phosphate pathway (glucose oxidation) and biosynthetic metabolism for cardiomyocytes proliferation

Summary​

As a biological pump, the heart needs to consume a substantial amount of energy to maintain sustained beating. Myocardial energy metabolism was recently reported to be related to the loss of proliferative capacity in cardiomyocytes (CMs). However, the intrinsic relationship between beating rate and proliferation in CMs and whether energy metabolism can regulate this relationship remains unclear. In this study, we find that moderate heart rate reduction (HRR) induces CM proliferation under physiological conditions and promotes cardiac regenerative repair after myocardial injury. Mechanistically, moderate HRR induces G1/S transition and increases the expression of glycolytic enzymes in CMs. Furthermore, moderate HRR induces a metabolic pattern switch, activating glucose metabolism and increasing the relative proportion of ATP production by the glycolytic pathway for biosynthesis of substrates needed for proliferative CMs. These results highlight the potential therapeutic role of HRR in not only acute myocardial protection but also long-term CM restoration.

Introduction​

Heart disease, including myocardial infarction (MI), is the leading cause of mortality worldwide (Derks and Bergmann, 2020). Massive loss of cardiomyocytes (CMs) and subsequent fibrosis after cardiac injury leads to heart failure and sudden cardiac death. Although current clinical therapies, such as percutaneous coronary intervention (PCI) and drug treatment, can reduce the rehospitalization and mortality rates of MI patients, they are unable to resolve the fundamental problem by reversing the loss of functional CMs (Hashimoto et al., 2018). Therefore, induction of cell cycle re-entry of terminally differentiated CMs is a promising therapeutic strategy for regeneration of the damaged heart.

Unlike the CMs of lower vertebrates, such as zebrafish and newts, mammalian CMs withdraw from the cell cycle shortly after birth and have a limited regenerative capacity that is insufficient to restore cardiac function following injury in adulthood (Bednarek et al., 2015; Bergmann et al., 2009; Cai et al., 2019; Porrello et al., 2011; Poss et al., 2002; Senyo et al., 2013; Wang et al., 2020; Ye et al., 2018; Zhu et al., 2018). The mechanism of the developmental transition from proliferative CMs in the perinatal period to nonproliferative CMs thereafter remains elusive.

CMs mainly utilize glycolysis for energy production in the embryonic stage, while fatty acid oxidation gradually assumes the function of energy production after birth (Gibb and Hill, 2018; Lalowski et al., 2018; Lopaschuk and Jaswal, 2010; Taegtmeyer et al., 2016). Interestingly, recent reports have indicated that this metabolic pattern switch is closely related to the loss of CM proliferation (Cardoso et al., 2020; Honkoop et al., 2019). However, the continuous beating of CMs requires a large amount of ATP. The unique energy metabolism of CMs may play an important role in maintaining sustained beating and the extremely low regenerative capacity of the heart. However, the intrinsic relationship between heartbeat and cardiac regeneration and whether myocardial energy metabolism regulates this relationship are unknown.

The heart rate fluctuates during different periods or pathophysiological states and varies between the perinatal period and adulthood. Epidemiologic studies show that a higher heart rate is an independent risk factor for cardiovascular diseases, such as ischemia, remodeling, and chronic heart failure (Bohm et al., 2015). In contrast, heart rate reduction (HRR) drugs, such as the beta-adrenergic blocker metoprolol and the If inhibitor ivabradine, have been shown to reduce the rehospitalization and mortality of chronic heart failure patients with reduced ejection fraction (Bhatt et al., 2017; Psotka and Teerlink, 2016) by reducing cardiac pressure load and oxygen consumption in patients (Ferrari and Fox, 2016; Tanna et al., 2019). However, the role of HRR in regulating CM proliferation and damaged heart repair has not been explored.

In this study, we provide a proof-of-concept demonstration that HRR promotes CM proliferation under both physiological and pathological conditions. Mechanistically, HRR induces a more neonatal-like metabolic status in CMs with increased utilization of glucose for energy production and biosynthesis and promotes the expression of many glycolytic enzymes that may stimulate cell cycle re-entry in CMs through their nonmetabolic functions.
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Discussion​

In this study, we demonstrated that moderate HRR can stimulate the metabolic pattern switch of CMs, increase the proportion of ATP generated by the glycolytic pathway, and increase the utilization of glucose by the PPP. These changes acted cooperatively with changes in metabolic enzymes to increase the transcription of cyclins to induce CM cell cycle re-entry and cardiac regeneration. This study represents a proof-of-concept demonstration that CM proliferation can be directly regulated by altering heart rate via a metabolic remodeling mechanism.

Glycolysis is the main metabolic pathway through which energy is supplied to the developing embryonic heart, while fatty acids oxidation are the main energy-producing mode in adult mammal heart (Bartelds et al., 2000; Gibb and Hill, 2018; Lopaschuk and Jaswal, 2010; Razeghi et al., 2001;Taegtmeyer et al., 2016). The metabolic switch from glycolysis to fatty acid oxidation shortly after birth accompanied by the simultaneous loss of the proliferative capacity of CMs (Cardoso et al., 2020; Lalowski et al., 2018) indicates that this metabolic pattern participates in the regulation of CM proliferation. However, evidence has shown that a shift from oxidative to glycolytic metabolism is required for cardiac myocyte hypertrophy and possibly proliferation in some contexts. In this regard, our studies aimed to assess external physiological inputs to further probe these potential mechanisms. Recently, researchers have begun to investigate the effects of changes in cardiac metabolism on CM proliferation. Enhanced glucose metabolism inhibits the maturation of CMs and promotes CM proliferation through the PPP (Nakano et al., 2017), and a switch to fatty acid oxidation via alteration of metabolic substrate utilization in a high oxygen environment is a driver of CM cell-cycle arrest (Mills et al., 2017). PKM2, a key glycolytic enzyme, has been reported to regulate the cell cycle and promote CM proliferation (Magadum et al., 2020; Ye et al., 2012). Nrg1/ErbB2 signaling induces CM proliferation through metabolic reprogramming (Honkoop et al., 2019). HK2, G6PD, PFKFB3, GAPDH, and PKM2, which were found to be regulated by HRR in our study, are all metabolic regulators that participate in cell-cycle progression in proliferative cells (Icard et al., 2019). In our study, we revealed that HRR stimulates a metabolic pattern switch, increasing the proportion of ATP generated from the glycolytic pathway and inducing biosynthesis to promote CM proliferation through the transcription of cyclins and CDKs. Thus, we concluded that activating glucose metabolism and an increase in the relative proportion of ATP generated from the glycolytic pathway can promote CM proliferation.

In addition to glucose-derived OXPHOS, our study showed that the PPP and biosynthetic metabolism were probably involved in HRR-mediated cardiac regeneration. PKM2 has been reported to redirect glucose carbon flow into the oxidative PPP, which reduces oxidative stress and oxidative damage, leading to increased expression of cell cycle genes in postnatal CMs (Magadum et al., 2020). Nakano et al., 2017 reported that high glucose can promote nucleotide biosynthesis in fetal heart through the PPP, resulting in a suppression of cardiac maturation. Their subsequent studies showed that overexpression of Glut1, an embryonic glucose transporter, can significantly increase in the glucose metabolites, including nucleotides for neonatal heart regeneration (Fajardo et al., 2021). As observed in our study, HRR can also activate the non-oxidative PPP, which contributes to the enhanced biosynthesis for proliferative CMs. Furthermore, a recent study showed that cardiac recovery in patients without left ventricular assist devices was associated with an increased flux of glucose into PPP to produce biomolecules (Badolia et al., 2020). Together, others and our data consistently show that PPP is involved in neonatal heart regeneration and may be an effective therapeutic target for heart injury.

A lower heart rate is beneficial in multiple cardiovascular diseases (Bohm et al., 2010, Bohm et al., 2015; Palatini, 2009). Clinically, a higher heart rate has been identified as an independent risk factor for cardiovascular diseases, while HRR has a beneficial effect on the prognosis of heart diseases (Bhatt et al., 2017; Psotka and Teerlink, 2016). In this study, we show that HRR, in addition to reducing cardiac pressure load and oxygen consumption (Custodis et al., 2008), can promote CM proliferation under both physiological and pathological conditions. Some studies have suggested an indirect link between heart rate and the proliferative ability of CMs. Mahmoud et al., 2015 found that nerves regulate CM proliferation in the injured hearts of both zebrafish and neonatal mice. In this study, drugs that inhibit cholinergic receptor to reduce CM proliferation also increased the heart rate. However, these studies did not explore the association between heart rate and CM proliferation, which we evaluated in our study.

In conclusion, we have identified HRR as a method for inducing CM proliferation in vitro and in vivo. Our research provides evidence that HRR is beneficial for the treatment of heart diseases. Theoretically, HRR induces cell cycle re-entry of CMs by stimulating the metabolic pattern switch, which further underlines the important impact of cardiac metabolism on CM proliferation.

 

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