tca cycle disruption  (MedChemExpress)

Journal: Signal Transduction and Targeted Therapy

Article Title: A two-strata energy flux system driven by a stress hormone prioritizes cardiac energetics

doi: 10.1038/s41392-025-02402-9

Figure Lengend Snippet: FGF21 deficiency alters systemic metabolites linked to mitochondrial and cardiac energetic defects. a – c Heatmap of significantly altered serum metabolites, including mitochondrial FAO precursors, fatty acids and oxylipins, TCA cycle intermediates, and nucleosides, in Fgf21 −/− (n = 3) and WT (n = 3) mice. p < 0.05; fold change (FC) > 1.5 or < 0.67. See also Fig. S a–c and S . For changes in serum phosphocreatine levels, see Fig. S . S, supplementary. d Experimental procedure for electrocardiogram analysis under anesthesia and anabiosis simulating ‘sleep’ (anesthesia on) and ‘awakening’ (anesthesia off) stages of torpor. ‘Sleep’, a sedentary state under anesthetic inhalation; Awakening, a recovery and active state following anesthetic removal. e Heart rate (HR) changes in Fgf21 −/− (n = 95) vs WT (n = 56) mice measured in d under normal conditions. BPM, beats per minute. f Area-under-curve (AUC) analysis of the HR excursion curves in e. See Fig. S . g , h Echocardiogram analysis of the mechano-energetic efficiency (MEE), ejection fraction (EF) and cardiac output (CO) of Fgf21 -/- (n = 51) vs WT (n = 51) mice. See Fig. S b-S for other Echo parameters. i Telemetry monitoring of HR changes over 24 hours in representative Fgf21 -/- vs WT mice under normal conditions. j AUC analysis of cumulative HR excursion curves of Fgf21 -/- (n = 6) vs WT (n = 6) mice in i. Changes in ambulatory movement and body temperature are shown in Fig. S j-S . k Representative TEM images of left ventricle cross-sections from Fgf21 -/- vs WT mice under normal conditions. Yellow arrowhead, mitochondria. Cyan arrowhead, Z line. See Fig. S for broader, low-magnification images. The changes in cardiac morphometric parameters, mild dilatation and insignificant fibrosis are shown in Fig. S . l Mitochondrial DNA content of hearts from Fgf21 -/- (n = 11-12) vs WT (n = 12) mice. m Catalytic activities of mitochondrial complexes I-IV in the hearts of Fgf21 -/- (n = 7-9) vs WT (n = 7-9) mice. h, hour. n , o HR Changes (n) with rhFGF21 treatment (n = 12) and AUC analysis (o) of Fgf21 -/- (n = 78) vs WT (n = 47) mice under normal conditions. p , q Changes in EF and LVSED with rhFGF21 treatment (n = 22) in Fgf21 -/- (n = 51) vs WT (n = 51) mice, as in n. See Fig. S g-S for other parameters. The data are presented as the means ± s.e.m.s. ( a – c , e – j ) Two-tailed unpaired Student’s t-test; ( l – q ) ordinary one-way ANOVA followed by Tukey’s test; * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001. *, Fgf21 -/- vs WT groups by Student’s t test or one-way ANOVA. $ , between treatment groups in WT mice. # , between treatment groups in Fgf21 -/- mice. All these also apply to other figures

Article Snippet: To establish a mouse model of TCA cycle disruption, 8-week-old Fgf21 -/- mice were fasted for 12 hours and then injected with Cpi-613 (1.0 mg/mouse, i.v .) (MedChemExpress, USA).

Techniques: Two Tailed Test

Journal: Signal Transduction and Targeted Therapy

Article Title: A two-strata energy flux system driven by a stress hormone prioritizes cardiac energetics

doi: 10.1038/s41392-025-02402-9

Figure Lengend Snippet: FGF21 orchestrates cardiac energy flux by engaging the LKB1-AMPK-mTOR energy stress pathways. a Transcriptomic enrichment of the LKB1-AMPK and mTOR energy regulation pathways in the hearts of fasted Fgf21 -/- (n = 3) vs WT (n = 3) mice and those with rhFGF21 treatment (n = 3). b Representative Western blot analysis of total kinase activities of cardiac LKB1, AMPK, and mTOR in the indicated mice (n = 3-6 for each group). Total kinase activity = (p-Kinase/Kinase) x (Kinase/Beta-actin), see also Fig. S . c Effects of cardiac-specific Stk11 (LKB1) ablation ( Stk11 f/f ;Myh6 Cre ) on HR. AUC analysis on the right. See Fig. S for experimental scheme, Fig. S for the AUC in the ‘Sleep’ and Awakening phases, and Fig. S29d for the Echo parameters. d Representative Western blot analysis of total kinase activities of cardiac AMPK, and mTOR in the indicated groups of mice (n = 3-6 for each group). See Fig. S . e Expression of representative genes involved in the TCA cycle, ETC, OXPHOS, and heart contraction in fasted Stk11 f/f ;Myh6 Cre and Fgf21 -/- mice 2 hours after rhFGF21 treatment. For changes in cardiac myofibrillar and mitochondrial structure, see Fig. S . Effects of mTOR inhibitor Torin-1 (0.05 mg per mouse, i.p .) on rhFGF21-induced HR improvements in fasted Fgf21 -/- mice (n = 11-12 per group). See Fig. S f, for experimental scheme and total AUC. Effects of Torin-1 and liver-specific Hmgcs2 deficiency on the cardiac ATP content in acute rhFGF21-treated Fgf21 -/- mice (n = 6 per group) following 12-h and 24-h fasts, respectively. h Effects of the AMPK activator AICAR (1.25 mg/mouse, i.p .) (n = 6) on rhFGF21-induced HR improvements in fasted Fgf21 -/- mice (n = 12 and 17, respectively). See Fig. S b-S for experimental scheme and total AUC, and Fig. S30d for the Echo parameters. i Transcriptomic enrichment of mitophagy, macroautophagy and associated LKB1-AMPK-mTOR energy stress pathways in the mice as in a. See Fig. S e, for mitophagy regulation by LKB1-AMPK-mTOR and autophagosome assembly. Data are means ± s.e.m.s; (d, e ) Two-tailed unpaired Student’s t-test; ( a – c , - i ) ordinary one-way ANOVA followed by Tukey’s test

Article Snippet: To establish a mouse model of TCA cycle disruption, 8-week-old Fgf21 -/- mice were fasted for 12 hours and then injected with Cpi-613 (1.0 mg/mouse, i.v .) (MedChemExpress, USA).

Techniques: Western Blot, Activity Assay, Expressing, Two Tailed Test

Journal: Signal Transduction and Targeted Therapy

Article Title: A two-strata energy flux system driven by a stress hormone prioritizes cardiac energetics

doi: 10.1038/s41392-025-02402-9

Figure Lengend Snippet: FGF21 deficiency induces a hypometabolic and mitochondrial hypoenergy state leading to cardiac dysfunction during fasting. a , Changes in mitochondrial metabolite/energy flux and key metabolic pathway enzymes involved in the TCA cycle, ETC and OXPHOS in Fgf21 -/- (n = 5-15) vs WT (n = 6-14) mice after 12 hours of fasting (fs) or 2 hours of rhFGF21 treatment, as analyzed by targeted cardiac energy metabolomics and qRT-PCR. See Fig. S for a summary heatmap. Transcriptomic and pathway enrichment in mitochondrial energy metabolism and cardiac function changes in Fgf21 -/- (n = 3) vs WT (n = 3) mice, with Reactome terms. For the GO-term and KEGG-term results, see Fig. , . For pathway enrichments in the Reactome term, GO term and KEGG term in Fgf21 -/- mice before and after rhFGF21 treatment, see Fig. S . For mitochondrial biogenesis, TCA cycle, ETC complexes I-IV, and OXPHOS, see Figs. S , S d, and S . For 24-h fasting effects, see Fig. S a– . d , e Significant pathway defects associated with striated muscle contraction and heart rate regulation in the hearts of Fgf21 -/- (n = 3) vs WT (n = 3) mice and pathway normalization after 2 hours of FGF21 treatment (n = 3). For cardiac conduction, blood vessel diameter maintenance, and blood pressure regulation, see Fig. S c–e and S . f Inhibiting the TCA cycle with Cpi-613 (1 mg/mouse, i.p .) reduced rhFGF21-promoted heart rate (HR) improvements in fasted Fgf21 -/- mice (same n = 6-16 mice per group). See Echo parameters in Fig. S . Data are means ± s.e.m.s; two-tailed unpaired Student’s t-test; a , , d – f ordinary one-way ANOVA followed by Tukey’s test. a , f images are generated in PowerPoint

Article Snippet: To establish a mouse model of TCA cycle disruption, 8-week-old Fgf21 -/- mice were fasted for 12 hours and then injected with Cpi-613 (1.0 mg/mouse, i.v .) (MedChemExpress, USA).

Techniques: Quantitative RT-PCR, Two Tailed Test, Generated

Journal: Signal Transduction and Targeted Therapy

Article Title: A two-strata energy flux system driven by a stress hormone prioritizes cardiac energetics

doi: 10.1038/s41392-025-02402-9

Figure Lengend Snippet: A mechanistic model for the regulation of heart energy allocation by energy stress hormone FGF21. The heart is an unrelenting bioengine that relies on a robust and uninterrupted influx of energy substates. Under physiologically relevant stressors, cardiomyocyte-derived or endocrine FGF21 acts to maintain heart rate, contractility, and hemodynamic stability by activating a dual energy flux system. Systemically, FGF21 directly promotes lipolysis in white adipose depots, releasing free fatty acids (FFAs) for liver uptake or direct transcardiac uptake via intracardiac microvascular circulation. It also promotes hepatic fatty acid oxidation and subsequent ketogenesis, supplying ketones for intracardiac ketolysis during prolonged fasting or starvation. These interorgan substrate mobilization effects ensure intracardiac energy substrate sufficiency. Locally, FGF21 signaling promotes transcardiac and intracardiac flux of various substrates for oxidative utilization, as well as cardiac mitochondrial biogenesis and respiration (the TCA cycle, ETC and OXPHOS), ensuring intracardiac ATP sufficiency. These processes/effects are mediated by the LKB1–AMPK and mTOR pathways and occur secondary to FGF21’s systemic actions. By coordinating these dual fuel systems, FGF21 signaling prioritizes incessant, robust intracardiac ATP flux, and thereby, cardiac energetic efficiency, particularly under stress. Thus, FGF21 is the first-known signaling factor for prioritizing cardiac energy needs and functional efficiency via a novel two-strata flux system. The image is generated in PowerPoint

Article Snippet: To establish a mouse model of TCA cycle disruption, 8-week-old Fgf21 -/- mice were fasted for 12 hours and then injected with Cpi-613 (1.0 mg/mouse, i.v .) (MedChemExpress, USA).

Techniques: Derivative Assay, Functional Assay, Generated