AMPK Signalling in Heart Failure: From Metabolic Sensor to Context-Dependent Therapeutic Target

Figures

• 

  Figure 1. AMPK heterotrimeric structure and isoform diversity. AMPK is a heterotrimeric serine/threonine kinase composed of one catalytic α-subunit and two regulatory subunits, β and γ. Each subunit exists as multiple isoforms (α1/α2, β1/β2, γ1/γ2/γ3), which combine to form distinct AMPK complexes with tissue-specific expression patterns and functional specialization. The schematic illustrates the structural organization of the AMPK complex, representative isoform combinations, and relative expression across metabolically active tissues including skeletal muscle, heart, liver, adipose tissue, brain, kidney, and colon. Differences in isoform composition contribute to context-dependent regulation of cellular metabolism and stress adaptation in health and disease.

• 

  Figure 2. AMPK signaling in heart failure: from energy sensing to cardiac remodelling. Energetic stress in heart failure—including hypoxia, ischemia, neurohormonal activation, and pressure/volume overload—promotes AMPK activation through increases in AMP/ATP and ADP/ATP ratios and upstream kinase signaling via LKB1 and CaMKKβ. Activated AMPK coordinates multiple adaptive metabolic pathways, including enhanced glucose uptake, fatty acid oxidation, mitochondrial biogenesis, autophagy/mitophagy, and antioxidant defenses, while suppressing hypertrophy, fibrosis, inflammation, and pathological remodeling. The figure also highlights the consequences of insufficient AMPK activity, which contributes to mitochondrial dysfunction, oxidative stress, adverse remodeling, and progression of heart failure.

• 

  Figure 3. Context-dependent AMPK activity in HFrEF, HFpEF, and diabetes. AMPK signaling differs substantially across major cardiometabolic phenotypes. In heart failure with reduced ejection fraction (HFrEF), reduced AMPK activity is associated with impaired oxidative metabolism and mitochondrial dysfunction. In heart failure with preserved ejection fraction (HFpEF), obesity, insulin resistance, inflammation, and mTOR activation contribute to dysregulated AMPK signaling and metabolic inflexibility. In diabetes, chronic nutrient excess and lipotoxicity impair SIRT1/PGC-1α/AMPK signaling, promoting ER stress, mitochondrial dysfunction, and cardiometabolic injury. The schematic emphasizes that the biological consequences of AMPK activation are highly phenotype-dependent and influenced by upstream metabolic context.

• 

  Figure 4. Therapeutic modulation of AMPK: opportunities and challenges. Multiple pharmacological and nutraceutical approaches modulate AMPK activity through distinct mechanisms. Indirect modulators such as metformin and SGLT2 inhibitors activate AMPK secondary to alterations in cellular energy balance, whereas direct activators including AICAR, PF-739, and MK-8722 bind AMPK and promote catalytic activation. Natural compounds such as resveratrol and berberine stimulate AMPK through upstream metabolic and redox pathways. The figure also summarizes key limitations of AMPK-targeted therapy, including limited isoform specificity, risks associated with chronic activation, off-target effects, and translational challenges. Future therapeutic strategies are expected to focus on α2-selective and cardiac-targeted AMPK modulation to maximize efficacy while minimizing systemic toxicity.