AMPK acts as a cellular energy receptor and regulates lipid metabolism and glucose metabolism. Under stress, such as hypoglycemia or hypoxia, the AMPK signaling pathway in cells is activated in response to changes in the AMP/ATP ratio, while the catabolic process of ATP production is promoted to restore the energy balance (9). The role of AMPK in HD is currently controversial. Certain studies have found that AMPK is activated as an adaptive and protective response in a number of models of cardiac injury such as pressure overload-induced cardiac hypertrophy or ischemia (10,11). However, mice with HF with preserved ejection fraction (HFpEF) show a significant reduction in AMPK activity (12). Cardiomyocyte-specific AMPK knockout mice can also develop left atrium (LA) remodeling and atrial fibrillation (12). Regardless of whether AMPK is activated or inhibited in HD, activating AMPK is considered a beneficial effect (13).

AMPK increases ATP production by promoting mitochondrial biogenesis (9). PGC-1α is the main regulatory factor for mitochondrial biogenesis (2). Further research has revealed that AMPK directly enhances the activity of PGC-1α by phosphorylating the threonine-177 and serine-538 sites of PGC-1α (14). When cells are subjected to oxidative stress, activation of the AMPK/PGC-1α signaling pathway promotes transcription of genes related to mitochondrial biogenesis and fatty acid oxidation to meet energy demands (15). In addition, AMPK promotes the activation of transcription factor EB to directly activate the promoter of the gene encoding PGC-1α (16). Therefore, the AMPK/PGC-1α signaling pathway plays important roles in metabolism homeostasis and HD.

Sirtuins (SIRT1-SIRT7), a family of NAD⁺-dependent protein-modifying enzymes, play an important role in cardiovascular diseases such as atherosclerosis, myocardial infarction, DIC and HF by regulating glucolipid metabolism, oxidative stress and inflammatory response (17). SIRT1, a major member of the SIRT family, is responsible for the deacetylation of PGC-1α in the nucleus. PGC-1α deacetylation can enhance binding ability using transcription factors, such as nuclear respiratory factor1/2 (NRF1/2), estrogen-related receptors or PPARs. Moreover, it can enhance cellular energy metabolism and oxidative stress capacity, adapting to different physiological conditions (18). SIRT1 can cause deacetylation and activation of liver kinase B1 to increase AMPK activation. AMPK activation increases SIRT1 activity through upregulation of NAD⁺ level (19). The interaction between AMPK and SIRT1 plays an important role in regulating physiological and pathological processes of the heart by regulating PGC-1α or other genes (13,20). In addition, SIRT3 can promote AMPK phosphorylation and increase PGC-1α activity (21). Ultimately, changes in PGC-1α activity will affect cardiac function.

The NF-κB signaling pathway is a central regulator of immunity and inflammation (22), which has recently emerged as important factors in a wide variety of HDs including atherosclerosis, cardiac remodeling and HF (23). Recent research has revealed that NF-κB and PGC-1α exert mutual regulatory effects. During inflammation, NF-κB signaling is activated and p65 binding to the PGC-1α promoter reduces PGC-1α expression and activity in a dose-dependent manner (24). This ultimately leads to downregulation of antioxidant target genes and the oxidative stress response. Simultaneously, oxidative stress will promote inhibitor kappa B alpha (IκBα) phosphorylation and subsequently increase p65 nuclear translocation, thereby exacerbating inflammatory factor release (25). Therefore, cross interaction between NF-κB and PGC-1α regulates the inflammatory response and HD.

Cardiac Ca²⁺ homeostasis is a key regulator of excitation-contraction coupling. Impaired Ca²⁺ homeostasis damages mitochondria and heart function, causing HF or other HDs (26). Ca²⁺-induced elevations in PGC-1α expression via the following mechanisms: i) p38 MAPK activation (27) and ii) AMPK phosphorylation activation (28). More direct evidence shows that cardiac-specific kinase-dead calcium/calmodulin-dependent protein kinase kinase-β mice leads to cardiac remodeling and HF through phosphorylation of AMPK and by upregulation of PGC-1α (29). Meanwhile, PGC-1α affects Ca²⁺ homeostasis by regulating Ca²⁺ release from the sarcoplasmic reticulum (SR) (30). Therefore, cross interaction between Ca²⁺ homeostasis and PGC-1α plays an important role in HD.

Pathological myocardial hypertrophy is the main predictive factor of the progression and poor prognosis of HD, usually related to HF. As expected, a heart-specific PGC-1α deficiency can result in HF and is considered a model of energy-related HF, which leads to the compromised utilization of both glucose and fatty acids as well as reduced mitochondrial function (7). PGC-1α dysregulation can also inhibit the recruitment of RNA polymerase II to metabolic gene promoters in HF, which might be another mechanism underlying a metabolic imbalance (7,40). Further research has shown that PGC-1α is associated with dilated HF, including changes in dyssynchronous local calcium release resulting from the disruption of t-tubular structures of cardiomyocytes, depending on energy metabolism (41). In addition, PGC-1α can mediate the control of mitochondrial quality and, thereby, the occurrence and development of HF by modulating mitochondrial dynamics, mitochondrial biogenesis and mitophagy (42). Fig. 1 shows a schematic diagram of the involvement of PGC-1α in pathological hypertrophy and HF.

CHD, also called ischemic heart disease, is one of the most common HDs. Its pathogenesis is mainly coronary artery stenosis or blockage caused by atherosclerosis (AS), which leads to long ischemic hypoxia or MI (43). Studies have demonstrated that PGC-1α plays a key role in endothelial damage, macrophage function and smooth muscle cell proliferation and migration by affecting oxidative stress, energy metabolism and inflammation (44–47). In addition, PGC-1α regulates MI or I/R injury via effects on ROS production, mitochondrial biogenesis, mitophagy and energy metabolism (48,49). Given the complex role of PGC-1α in CHD, fully understanding its function in different cells will provide a basis for the future application of PGC-1α agonists. A promising advantage of PGC-1α agonists is the ability to improve multiple pathological pathways in CHD.

The pathological mechanism underlying AS relies on an imbalance between blood flow and energy expenditure, leading to the impairment of endothelial function, mononuclear macrophage infiltration and vascular smooth muscle cell (VSMC) proliferation and migration (50). Research shows that the overexpression of PGC-1α in coronary artery disease (CAD) vessels increases vascular intraluminal pressure and exerts a therapeutic effect in patients with CAD via a shift from mitochondria-derived hydrogen peroxide to nitric oxide (NO)-mediated vasodilation (51). These results indicate that PGC-1α is a promising target for treating AS. Fig. 2 shows a summary of the aforementioned data.

Endothelial dysfunction is considered a gatekeeper of vascular diseases and one of the signs of AS (52). PGC-1α participates in the regulation of endothelial function by maintaining vascular tension and via antioxidant and anti-inflammatory factors. For example, PGC-1α can activate the phosphatidylinositol 3-kinase/AKT signaling pathway, leading to the decrease of endothelial nitric oxide synthase (eNOS) serine 1177 phosphorylation and NO production; this maintains vascular tension (53). Additionally, PGC-1α can combine with Nrf2 to form a complex that exerts antioxidant effects and inhibits endothelial dysfunction caused by high glucose/oxidation low lipoprotein (oxLDL) (45). PGC-1α can inhibit NF-κB signaling and reduce monocyte chemoattractant protein 1 and vascular cellular adhesion molecule-1 (VCAM-1) expression in endothelial cells, which can lead to a decrease in monocyte aggregation and slow the progression of AS. Meanwhile, PGC-1α inhibits ROS production by regulating the NF-κB and VEGFA signaling pathways and alleviating oxidative stress and inflammatory responses (46,54).

The presence of macrophages is an obvious sign of atherosclerotic plaque. Increased levels of inflammatory factors, such as vascular VCAM-1 and intercellular adhesion molecules, can mediate the adhesion between the surface of monocytes and the endothelium, leading to the recruitment of monocyte-derived cells under the endothelium and differentiation into macrophages. Macrophages engulf excessive oxidized lipoproteins under the endothelium and eventually become foam cells, a sign of ‘fat streaks’ and early atherosclerotic plaques (55). A study has shown that PGC-1α inhibits adhesion molecule gene expression and cell adhesion (56). Furthermore, the overexpression of PGC-1α inhibits oxLDL uptake in macrophages. By contrast, the macrophage-specific deletion of PGC-1α accelerates atherosclerosis in LDLR^−/− mice by promoting foam cell formation (47).

In addition to endothelial cells and macrophages, VSMC proliferation and migration play important roles in vascular homeostasis. Reports show that PGC-1α inhibits VSMC proliferation and migration by attenuating NOX1 or upregulating the antioxidant enzyme superoxide dismutase (SOD)2 to mediate the generation of ROS and prevent extracellular signal-regulated kinase 1/2 phosphorylation (57–59).

The damage caused to the myocardium during MI is the result of two processes: Ischemia and subsequent reperfusion. Cardiac tissue will go through two phases after MI: Inflammatory phase (3 h to 7 days) and repair phase (7–21 days) (60). When subjected to hypoxic pressure, the mitochondrial function of myocardial cells is impaired and NF-κB p65 activation increases, thereby silencing PGC-1α promoter activity (24). Transcriptomics analysis has shown that the enrichment of PPAR/retinoid X receptor binding sites is decreased and levels of the target gene PGC-1α are lower in post-MI border zone tissues than they are in the healthy left ventricle 7 days after infarction (61). In animal models of I/R, PGC-1α expression is reduced at 3 days but partially recovers at 16 days in the infarcted area, with no changes in remote areas (62). Lou et al (63) discovered that infarct-remodeled hearts (6 weeks after infarction) show activation of fatty acid β-oxidation and mobilization of fatty acids from the endogenous triglycerides store via increased PPARα/PGC-1α signaling. These results suggest that the activation of NF-κB may inhibit the expression of PGC-1α during the inflammatory phase of MI. PGC-1α expression gradually recovers after inflammation disappears. To maintain the energy required by the heart, it is hypothesized that PGC-1α expression may be elevated in infarct-remodeled hearts. More evidence is needed to verify this hypothesis.

Mitochondrial ROS (mROS) and Ca²⁺ overload are particular drivers of I/R injury, resulting in mitochondrial permeability transition pore opening, cell death and ventricular remodeling (64). Ischemic preconditioning is the most powerful intervention for reducing MI size before reperfusion. Chronic intermittent hypobaric hypoxia (CIHH) treatment can reduce the calcium overload and hypoxia/reoxygenation injury in cardiomyocytes by upregulating the expression of PGC-1α and regulating glucose and lipid metabolism (65). Meanwhile, PGC-1α mediates the elimination of ROS by binding to and co-activating NRF1/2 and its downstream genes (66). In addition, PGC-1α inhibits myocardial apoptosis by promoting SIRT3 expression (67). Overall, PGC-1α prevents IR damage by reducing mROS production and cell apoptosis.

PGC-1α participates in the regulation of MI risk factors, including low adiponectin (APN) levels and an increased risk of type 2 diabetes in patients with MI (68). APN activates AMPK-PGC-1α signaling in cardiomyocytes and reduces apoptosis to protect against post-MI remodeling and dysfunction (69). PGC-1α expression is increased in blood mononuclear cells of patients with st-elevated myocardial infarction and the expression level was correlated with the infarct size (70). These results indicate that PGC-1α plays an important role in MI or I/R and may serve as a blood marker for MI. Fig. 3. shows a schematic diagram of the involvement of PGC-1α in the process of MI and I/R.

DCM refers to myocardial disease that occurs in patients with diabetes and cannot be explained by hypertensive heart disease, coronary atherosclerotic heart disease, heart valve disease and other HDs. The PPARα/PGC-1α pathway plays an important role in the occurrence and development of DCM by promoting metabolic inflexibility. In the early diabetic heart, PPARα and PGC-1α are activated to increase fatty acid oxidation and lipid uptake rates, instead of glucose oxidation (71). This leads to increased ATP generation and a decreased AMP/ATP ratio, which leads to AMPK inactivation and subsequent PGC-1α inhibition, ultimately resulting in an excessive supply of fatty acids and lipid accumulation in the DCM heart (9,72). Cardiac lipotoxicity will lead to increased total ceramide levels. The accumulation of ceramides in the heart leads to oxidative stress and mitochondrial dysfunction by inhibiting PGC-1α, PPARα and CD36 expression (72,73).

PGC-1α also participates in the pathological mechanism of DCM by regulating ROS production, inflammatory response and Ca²⁺ homeostasis. On one hand, PGC-1α can interact with heme-oxygenase-1 to improve antioxidant defense by ROS clearance (74). The anti-DCM effect has been validated in caloric restriction and exercise models by activating the AMPK/SIRT1/PGC-1α signaling pathway (75,76). Moreover, moderate overexpression of PGC-1α maintains Ca²⁺ homeostasis by increasing the expression of sarcoplasmic/endoplasmic reticulum Ca²⁺ transporting ATPase 2 (77). Fig. 4 shows a schematic diagram of the involvement of PGC-1α in DCM.

Cardiotoxicity caused by drugs is essentially a harmful reaction in the heart that occurs during drug use. For example, the cardiotoxicity produced by the anti-cancer agent doxorubicin limits its wide clinical applications. Energy homeostasis, oxidative stress, apoptosis and mitophagy disorders are considered the main factors associated with cardiotoxicity (78,79). PGC-1α mainly functions in the myocardium by participating in energy metabolism and mitochondrial oxidative stress. PGC-1α can also affect the production of ROS, mitochondrial biogenesis, mitochondrial autophagy and ultimately cell apoptosis through NRF2 (80). A recently discovered function of PGC-1α is the ability to promote autophagy and inhibit apoptosis by binding to nucleolin (81). At present, certain drugs have shown protective effects in DIC by upregulating PGC-1α, such as hydropersulfides and the hydroethanolic extract of Cirsium (80,82). In the future, the aim will be to identify drugs for treating DIC by upregulating PGC-1α.

Cardiac rhythm is controlled by various ion channels and electrogenic ion transporters. Intracellular sarcoplasmic reticulum and mitochondria regulate these channel and transporter changes (83). Recent research has shown that PGC-1α participates in the occurrence and development of arrhythmia. A transcription profiling analysis of PGC-1α^−/− mouse atrial tissues showed that genes related to Na⁺-K⁺-ATPase activity, hyperpolarized activation of cyclic nucleotide gated ion channels, Na⁺ channel-dependent action potential activation and propagation, Ca²⁺ current generation and Ca²⁺ homeostasis were downregulated. Compared with the levels in wild-type mice, Na_V1.5 channel protein expression is reduced, while the gap junction protein expression remains unchanged (84). In PGC-1α^−/− mouse ventricular tissues, genes related to Na⁺-/K⁺- ATPase activity, Ca²⁺ influx, action potential repolarization, autonomous function and morphological characteristics are also downregulated. The expression of Na_V1.5 decreases and tissue fibrosis increases (85). Naumenko et al (41) specifically knocked out myocardial PGC-1α and found that mice exhibit dilated HF and myocardial electrophysiological remodeling related to energy metabolism inhibition, with abnormal SR absorption and release of Ca²⁺. The findings of previous research confirm that PGC-1α participates in cardiac electrophysiology, provides substrates for the occurrence of arrhythmia and may be related to Na⁺/Ca²⁺ homeostasis (84–86).