bims-hafaim 2023-08-06 papers

Issue of 2023–08–06
five papers selected by
Kyle McCommis, Saint Louis University

iScience. 2023 Jul 21. 26(7): 107131

Increased cardiac PFK-2 protects against high-fat diet-induced cardiomyopathy and mediates beneficial systemic metabolic effects.

Maria F Mendez Garcia, Satoshi Matsuzaki, Albert Batushansky, Ryan Newhardt, Caroline Kinter, Yan Jin, Shivani N Mann, Michael B Stout, Haiwei Gu, Ying Ann Chiao, Michael Kinter, Kenneth M Humphries.

A healthy heart adapts to changes in nutrient availability and energy demands. In metabolic diseases like type 2 diabetes (T2D), increased reliance on fatty acids for energy production contributes to mitochondrial dysfunction and cardiomyopathy. A principal regulator of cardiac metabolism is 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2), which is a central driver of glycolysis. We hypothesized that increasing PFK-2 activity could mitigate cardiac dysfunction induced by high-fat diet (HFD). Wild type (WT) and cardiac-specific transgenic mice expressing PFK-2 (GlycoHi) were fed a low fat or HFD for 16 weeks to induce metabolic dysfunction. Metabolic phenotypes were determined by measuring mitochondrial bioenergetics and performing targeted quantitative proteomic and metabolomic analysis. Increasing cardiac PFK-2 had beneficial effects on cardiac and mitochondrial function. Unexpectedly, GlycoHi mice also exhibited sex-dependent systemic protection from HFD, including increased glucose homeostasis. These findings support improving glycolysis via PFK-2 activity can mitigate mitochondrial and functional changes that occur with metabolic syndrome.

Keywords: Metabolomics; Molecular biology; Physiology; Proteomics

DOI: https://doi.org/10.1016/j.isci.2023.107131

Physiol Rep. 2023 Aug;11(15): e15742

Impaired cardiac glycolysis and glycogen depletion are linked to poor myocardial outcomes in juvenile male swine with metabolic syndrome and ischemia.

Mark Broadwin, Dwight D Harris, Sharif A Sabe, Elif Sengun, Amber J Sylvestre, Boian S Alexandrov, Frank W Selke, Anny Usheva.

Obesity continues to rise in the juveniles and obese children are more likely to develop metabolic syndrome (MetS) and related cardiovascular disease. Unfortunately, effective prevention and long-term treatment options remain limited. We determined the juvenile cardiac response to MetS in a swine model. Juvenile male swine were fed either an obesogenic diet, to induce MetS, or a lean diet, as a control (LD). Myocardial ischemia was induced with surgically placed ameroid constrictor on the left circumflex artery. Physiological data were recorded and at 22 weeks of age the animals underwent a terminal harvest procedure and myocardial tissue was extracted for total metabolic and proteomic LC/MS-MS, RNA-seq analysis, and data underwent nonnegative matrix factorization for metabolic signatures. Significantly altered in MetS versus. LD were the glycolysis-related metabolites and enzymes. In MetS compared with LD Glycogen synthase 1 (GYS1)-glycogen phosphorylases (PYGM/PYGL) expression disbalance resulted in a loss of myocardial glycogen. Our findings are consistent with the concept that transcriptionally driven myocardial changes in glycogen and glucose metabolism-related enzymes lead to a deficiency of their metabolite products in MetS. This abnormal energy metabolism provides insight into the pathogenesis of the juvenile heart in MetS. This study reveals that MetS and ischemia diminishes ATP availability in the myocardium via altering the glucose-G6P-pyruvate axis at the level of metabolites and gene expression of related enzymes. The observed severe glycogen depletion in MetS coincides with disbalance in expression of GYS1 and both PYGM and PYGL. This altered energy substrate metabolism is a potential target of pharmacological agents for improving juvenile myocardial function in MetS and ischemia.

Keywords: myocardial metabolomics; nonnegative matrix factorization; proteomics; swine model of metabolic syndrome

DOI: https://doi.org/10.14814/phy2.15742

Circulation. 2023 Aug 03.

Cardiac and Metabolic Effects of Dapagliflozin in Heart Failure With Preserved Ejection Fraction: The CAMEO-DAPA Trial.

Barry A Borlaug, Yogesh N V Reddy, Amanda Braun, Hidemi Sorimachi, Massar Omar, Dejana Popovic, Alessio Alogna, Michael D Jensen, Rickey Carter.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors reduce risk of hospitalization for heart failure in patients who have heart failure with preserved ejection fraction (HFpEF), but the hemodynamic mechanisms underlying these benefits remain unclear. This study sought to determine whether treatment with dapagliflozin affects pulmonary capillary wedge pressure (PCWP) at rest and during exercise in patients with HFpEF.
METHODS: This was a single-center, double-blinded, randomized, placebo-controlled trial testing the effects of 10 mg of dapagliflozin once daily in patients with HFpEF. Patients with New York Heart Association class II or III heart failure, ejection fraction ≥50%, and elevated PCWP during exercise were recruited. Cardiac hemodynamics were measured at rest and during exercise using high-fidelity micromanometers at baseline and after 24 weeks of treatment. The primary end point was a change from baseline in rest and peak exercise PCWPs that incorporated both measurements, and was compared using a mixed-model likelihood ratio test. Key secondary end points included body weight and directly measured blood and plasma volumes. Expired gas analysis was performed evaluate oxygen transport in tandem with arterial lactate sampling.
RESULTS: Among 38 patients completing baseline assessments (median age 68 years; 66% women; 71% obese), 37 completed the trial. Treatment with dapagliflozin resulted in reduction in the primary end point of change in PCWP at rest and during exercise at 24 weeks relative to treatment with placebo (likelihood ratio test for overall changes in PCWP; P<0.001), with lower PCWP at rest (estimated treatment difference [ETD], -3.5 mm Hg [95% CI, -6.6 to -0.4]; P=0.029) and maximal exercise (ETD, -5.7 mm Hg [95% CI, -10.8 to -0.7]; P=0.027). Body weight was reduced with dapagliflozin (ETD, -3.5 kg [95% CI, -5.9 to -1.1]; P=0.006), as was plasma volume (ETD, -285 mL [95% CI, -510 to -60]; P=0.014), but there was no significant effect on red blood cell volume. There were no differences in oxygen consumption at 20-W or peak exercise, but dapagliflozin decreased arterial lactate at 20 W (-0.70 ± 0.77 versus 0.37 ± 1.29 mM; P=0.006).
CONCLUSIONS: In patients with HFpEF, treatment with dapagliflozin reduces resting and exercise PCWP, along with the favorable effects on plasma volume and body weight. These findings provide new insight into the hemodynamic mechanisms of benefit with sodium-glucose cotransporter-2 inhibitors in HFpEF.
REGISTRATION: URL: https://www.
CLINICALTRIALS: gov; Unique identifier: NCT04730947.

Keywords: diastolic pressure; exercise; heart failure

DOI: https://doi.org/10.1161/CIRCULATIONAHA.123.065134

EMBO Mol Med. 2023 Aug 03. e17399

Metabolic switch from fatty acid oxidation to glycolysis in knock-in mouse model of Barth syndrome.

Mitochondria are central for cellular metabolism and energy supply. Barth syndrome (BTHS) is a severe disorder, due to dysfunction of the mitochondrial cardiolipin acyl transferase tafazzin. Altered cardiolipin remodeling affects mitochondrial inner membrane organization and function of membrane proteins such as transporters and the oxidative phosphorylation (OXPHOS) system. Here, we describe a mouse model that carries a G197V exchange in tafazzin, corresponding to BTHS patients. TAZG197V mice recapitulate disease-specific pathology including cardiac dysfunction and reduced oxidative phosphorylation. We show that mutant mitochondria display defective fatty acid-driven oxidative phosphorylation due to reduced levels of carnitine palmitoyl transferases. A metabolic switch in ATP production from OXPHOS to glycolysis is apparent in mouse heart and patient iPSC cell-derived cardiomyocytes. An increase in glycolytic ATP production inactivates AMPK causing altered metabolic signaling in TAZG197V . Treatment of mutant cells with AMPK activator reestablishes fatty acid-driven OXPHOS and protects mice against cardiac dysfunction.

Keywords: Barth syndrome; cardiolipin; cardiomyopathy; mitochondria; tafazzin

DOI: https://doi.org/10.15252/emmm.202317399

Pharmazie. 2023 Jul 01. 78(6): 100-105

Effect of Sodium-Glucose Cotransporter-2 Inhibitor Administration on Cardiac Rehabilitation in Patients with Type 2 Diabetes Mellitus with Heart Failure.

S Nakamura, E Tanaka, Y Iso, H Fujihara.

Cardiac rehabilitation in patients with diabetes mellitus and heart failure may be affected by anti-diabetic drugs. However, there are few reports on the effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors on cardiac rehabilitation. Thus, we retrospectively investigated the patient backgrounds and effects of cardiac rehabilitation in 44 patients admitted to our hospital with heart failure and pre-existing diabetes mellitus. Our results showed that the patients tended to be older, and those who received SGLT2 inhibitors had lower systolic blood pressure and left ventricular ejection fraction on admission than those who did not. Cardiac rehabilitation significantly improved the Short Physical Performance Battery (SPPB) score in all patients, and there was no significant difference in body mass index or in body weight. There were no significant differences in SPPB score at admission, discharge, or change from admission to discharge with or without SGLT2 inhibitors. These results suggest that SGLT2 inhibitors do not affect the change in SPPB scores. SGLT2 inhibitors may thus be used safely without affecting cardiac rehabilitation while adhering to the necessary safety precautions.

DOI: https://doi.org/10.1691/ph.2023.3531