bims-hafaim 2026-04-19 papers

Issue of 2026–04–19
four papers selected by
Kyle McCommis, Saint Louis University

Metabolism. 2026 Apr 11. pii: S0026-0495(26)00129-0. [Epub ahead of print]180 156619

Loss of cardiomyocyte AKT signaling causes deterioration of lipid metabolism and cellular atrophy.

Stefanie Gödecke, André Heinen, Tim Appel, Phil-Torben Müller, Tim Stemmer, Daniela Müller, Uli Flögel, Diran Herebian, Fiorella A Solari, Rene Deenen, Karl Köhrer, Albert Sickmann, Axel Gödecke.

The mammalian heart critically depends on oxidative metabolism of fatty acids, glucose, ketones, and amino acids to meet its extensive ATP demands. AKT/protein kinase B plays a central role in regulating cell growth and metabolism by coordinating an anabolic metabolism in response to insulin or IGF1, particularly by elevating glucose uptake and mTOR activity. Here, we investigated the effect of simultaneous deletion of the two major cardiac isoforms AKT1 and AKT2 on the function and metabolism of the adult mouse heart. Inducible cardiomyocyte specific AKT1 AKT2 double knockout mice developed a rapidly progressing and lethal heart failure with extensive cardiomyocyte atrophy. Metabolic analyses of substrate-specific respiration of mitochondria (respirometry) and of isolated cardiac tissue (Seahorse flux analysis) demonstrated that fatty acid metabolism was severely compromised, whereas glucose metabolism was less affected. Volume-specific in vivo NMR spectroscopy and CrCEST (Creatine chemical exchange saturation transfer) imaging revealed a drop of the cardiac phosphocreatine/ATP ratios from 2 to 1.5, indicating severe energetic depletion. Transcriptomic and proteomic studies showed that genes of the TCA cycle, β-oxidation, and oxidative phosphorylation were coordinately down-regulated. Moreover, AKT1/AKT2 deficient cardiomyocytes lost the ability to store fatty acids in lipid droplets (LDs) due to an early loss of perilipins and other proteins involved in LD generation and function. In conclusion, our data show that general, isoform-independent AKT signaling in cardiac myocytes is indispensable for preservation of cardiac fatty acid metabolism and energy supply.

Keywords: AKT signaling; Cardiac atrophy; Cardiac lipid metabolism; Heart failure; Perilipins

DOI: https://doi.org/10.1016/j.metabol.2026.156619

Eur J Pharmacol. 2026 Apr 15. pii: S0014-2999(26)00355-9. [Epub ahead of print]1023 178873

IGF-1 attenuates high fat diet-elicited cardiomyopathy via arachidylcarnitine-dependent suppression of ferroptosis and mitochondrial dysfunction.

Lin Wang, Mingzhi Shen, Miyesaier Abudureyimu, Hua Ye, Jie Lin, Altaf A Abdulkhaliq, Russel J Reiter, Feng Dong, Guanmou Li, Maolong Dong, Rongjun Zou, Ming Yuan, Ling Lin, Jun Ren.

Obesity is associated with low circulating IGF-1 levels, mitochondrial injury, and myocardial anomalies, however, the precise interplay between IGF-1 and obesity cardiomyopathy remains unclear. Our work evaluated the impact of IGF-1 on high fat (HF) diet-evoked alterations in cardiac geometry, function, and mitochondrial integrity. WT and cardiac-specific IGF-1 transgenic mice were offered a low fat (LF, 10% fat calorie) or HF (60% fat calorie) diet for 20 weeks before assessing glucose sensitivity, plasma profiles, myocardial remodeling and function, ROS, mitochondrial integrity, and cell death. Transcriptomic analyses of obese human and murine hearts revealed that obesity cardiomyopathy was characterized by significant metabolic reprogramming, marked by a shift from TCA cycle to glycolysis and disrupted fatty acid homeostasis, alongside identification of ferroptosis as a key regulatory node in myocardial injury. HF led to hyperleptinemia, hypertriglyceridemia, reduced plasma IGF-1, and glucose intolerance, cardiac hypertrophy (higher LV dimensions, wall thickness), interstitial fibrosis, contractile dysfunction (lower fractional shortening, ejection fraction, cell contractile and intracellular Ca2+ derangement), oxidative stress, apoptosis, ferroptosis, and mitochondrial injury (declined PGC1α and UCP-2). Notably, cardiac-specific IGF-1 overexpression mitigated HF-induced myocardial remodeling, dysfunction, mitochondrial injury, and ferroptosis, without affecting systemic glucose metabolism or plasma profiles. Importantly, targeted metabolomics revealed a distinct plasma acylcarnitine signature in obese patients, with C20:0 (arachidylcarnitine) identified as a top discriminative metabolite. Furthermore, reduced myocardial L-carnitine level was observed in HF-fed mice, and L-carnitine supplementation rescued HF-induced cardiac geometric, functional, and mitochondrial anomalies. These data indicate that IGF-1 confers beneficial effect for chronic HF intake-induced damage possibly via preserved mitochondrial integrity, suppressed ferroptosis, and restored arachidylcarnitine levels, highlighting a metabolomic-metabolic axis in obesity-related cardiac dysfunction.

Keywords: Arachidylcarnitine; Fat diet; Ferroptosis; Heart; IGF-1; Mitochondria

DOI: https://doi.org/10.1016/j.ejphar.2026.178873

Front Cardiovasc Med. 2026 ;13 1781927

Pathogenic role of mitochondrial DNA mutations in heart failure: clinical features, mechanisms, and therapeutic prospects.

Mingyang Ni, Aijia Zheng, Hang Zheng, Wenqing Jia, Yuansheng Wang, Yuqing Peng, Chenguang Yao, Yanhong Wei, Xueli Wang, Sini Kang.

Heart failure (Heart failure, HF) is a complex clinical syndrome caused by any abnormality in the structure or function of the heart, resulting in impaired ventricular filling or ejection capacity, with mitochondrial dysfunction recognized as one of the key pathological foundations. In recent years, numerous studies have demonstrated that mitochondrial DNA (mtDNA) mutations play a significant role in cardiomyopathy and HF; however, systematic understanding of their modes of action in disease progression remains limited. Most studies have attributed the pathogenic effects of mtDNA mutations to impaired energy metabolism, emphasizing the consequences of defective oxidative phosphorylation and insufficient ATP production on myocardial function. Emerging evidence, however, indicates that mtDNA mutations also contribute to the development and progression of HF by inducing reactive oxygen species accumulation, disrupting mitochondrial structural and dynamic homeostasis, and activating innate immune inflammatory signaling pathways. Furthermore, variations in mtDNA mutation load and heteroplasmy levels constitute an important molecular basis for the diverse clinical phenotypes of HF, although the underlying mechanisms have yet to be systematically integrated. This review comprehensively summarizes the pathogenic mechanisms of cardiac mtDNA mutations and their heteroplasmy in HF, with particular emphasis on the intrinsic links among mitochondrial metabolic reprogramming, oxidative stress, immune activation, and myocardial remodeling, and outlines potential diagnostic and therapeutic strategies based on mitochondrial dysfunction and mtDNA stability.

Keywords: cardiomyopathy; energy metabolism; heart failure; immune activation; mitochondrial DNA mutations; mitochondrial dysfunction; oxidative stress; therapeutic strategies

DOI: https://doi.org/10.3389/fcvm.2026.1781927

Npj Imaging. 2026 Apr 16. pii: 28. [Epub ahead of print]4(1):

[3-11C]Pyruvate PET detects alterations in cardiac pyruvate metabolism induced by doxorubicin chemotherapy.

Chul-Hee Lee, Thomas Ruan, Shuvra Debnath, Anja S Wacker, Grace Figlioli, John W Babich, Sadek A Nehmeh, Kayvan R Keshari, James M Kelly.

Changes in cardiac metabolism typically precede cardiac dysfunction and therefore represent an important target for diagnosis and treatment designed to prevent progression to heart failure, a leading cause of death. Profound changes in pyruvate metabolism, including reduced expression of the mitochondrial pyruvate carrier (MPC), are increasingly recognized as early maladaptive alterations in cardiomyopathies, but no methods currently exist to determine MPC expression in vivo. We exposed mice to doxorubicin (DOX), an anthracycline chemotherapeutic known to perturb pyruvate metabolism, and demonstrated that cardiac tissue levels of MPC decrease within 4 weeks of initial DOX exposure. Using a combination of stable isotope tracing metabolomics, hyperpolarized [1-13C]pyruvate magnetic resonance imaging (MRI), and [3-11C]pyruvate positron emission tomography (PET), we found that loss of MPC and monocarboxylate transporter 1 (MCT1) resulted in decreased utilization of pyruvate for mitochondrial oxidative metabolism and resulted in decreased cardiac carbon-11 clearance. Despite recovery of expression levels of pyruvate transporters, including MPC, 16 weeks after initial DOX exposure, cardiac carbon-11 clearance still trends towards differences between control mice and the mice exposed to this chemotherapeutic. [3-11C]Pyruvate PET is therefore a promising approach to imaging cardiac pyruvate transport with potential applications to the identification of early maladaptive changes in pyruvate metabolism and monitoring response to therapy.

DOI: https://doi.org/10.1038/s44303-026-00165-8