Table 1:
Overview of genetically engineered mouse models mimicking or exhibiting dysregulated cardiac metabolism.
| Metabolic Pathway | Loss-of-function | Gain-of-function |
|---|---|---|
| FA uptake | CD36-KO, cmCD36-KO (+ aging); ACSL1-KO, cmACSL1-KO | CD36-OE (in SHR rats), cmFATP1-OE, ACSL1-OE, cmACSL1-OE |
| Triglyceride synthesis and lipolysis | cmDGAT1-KO; ATGL-KO (+ STZ), cmATGL-KO; LPL-KO, cmLPL-KO | cmDGAT1-OE; cmATGL-OE (+ HFD/high-sugar diet or STZ); LpL-OE, cmLpL-OE |
| Mitochondrial FA transport | ACC2-KO, ACC2-KI (mutant), cmACC2-KO; MCD-KO (+ HFD or aging); CPT1b-KO | L-CPT1-OE |
| FA oxidation: | VLCAD-KO, cmVLCAD-KO; LCAD-KO | |
| Regulators of energy metabolism | PGC1α-KO (+ HFD or in ob/ob mice); PGC1β-KO; PGC1α/β-KO (in ob/ob mice), cPGC1α/β-KO; TFAm-KO, cmTFAm-KO; POLGA-KO, cmMTERF3-KO; cmTFB1M-KO; NRF1-KO, efNRF2-KO; ERRα-KO, ERRγ-KO, cm ERRγ-KO, ERRα/cmERRγ-KO; PPARα-KO (+ STZ or HFD or in UCP-DTA mice); cmPPARδ-KO; PPARγ-KO, cmPPARγ-KO; AMPKα2-KO (+ calorie restriction); AMPKα2-OE (mutant), AMPKγ2-OE (mutant: N488I) | cmPGC1α-OE; TFAm-OE; cERRγ-OE; cmERRγ-OE; cmPPARα-OE (+ HFD or STZ); cmPPARγ-OE |
| Glucose utilization | PDK4-KO (+ HFD); cmPDK4-KO; cmGLUT1-KO, GLUT4-KO, cmGLUT4-KO (+ exercise), cmMPC1-KO, cm-MPC2-KO | cPDK4-OE; cmGLUT1-OE (+ HFD), GLUT4-OE (in db/db mice), cmGLUT4-OE (+ STZ); cPFK2-OE |
| Insulin/IGF1 signaling | CIRKO (+ exercise or STZ), cIRS1/2-KO, cIRS1-KO (+ exercise), cIRS2-KO (+ exercise); cmPI3K-KO; AKT1-KO (+ exercise), AKT2-KO (+ exercise), cmAKT-KO; cmIGF1R-KO (+ aging or + exercise); CIGF/IR-KO | cPI3K-OE; cmAKT-OE; IGF1R-OE; IGF-IIRα-OE |
| Ketone body utilization | cmBDH1-KO; SCOT-KO, cmSCOT-KO | cmBDH1-OE |
| BCAA utilization | cmBCATm-KO; KLF15-KO; PP2Cm-KO | SLC25A44-OE |
| Posttranslational regulation | SIRT1-KO (+ exercise), SIRT1-KO (+ HFD), SIRT3-KO (+ STZ or HFD/DOCA or HFD/L-NAME), ecSIRT3-KO, CrAT/SIRT3-KO; SIRT4-KO; SIRT5-KO, cmSIRT5-KO; SIRT6-KO, cmSIRT6-KO; SIRT7-KO, cmSIRT7-KO; cmOGT-KO, cmOGA-KO | SIRT1-OE, SIRT1/PPARα-OE, SIRT3-OE (in db/db mice); SIRT4-OE; SIRT6-OE (+ HFHS diet), cmSIRT6-OE |
| Mitochondrial dynamics | MFN1/2-KO, cmMFN1/2-KO, cmMFN1-KO, cmMFN2-KO; cmDRP1-KO; OPA1-KO; cmTME1L-KO; DRP1/MFN1/2-KO | cmDRP1-OE |
See extended version and references in Supplemental Table S2.
Abbreviations: ACC, acetyl-CoA carboxylase; AKT, protein kinase B; AMPK, adenosine monophosphate-activated protein kinase; ACSL, acyl-CoA synthetase, long chain; BCAA, branched chain amino acid; BCATm, branched-chain aminotransferase, mitochondrial; BDH, β-hydroxybutyrate dehydrogenase; CD36, fatty acid transporter; cm, cardiomyocyte; CIRKO – cardiomyocyte KO of insulin receptor, cIRS(1/2)1KO cardiomyocyte KO of insulin receptor substrates (1/2); CPT, carnitine palmitoyltransferase; CrAT, carnitine palmitoyl transferase; DGAT, diacylglycerol acyltransferases; DOCA, deoxycorticosterone acetate; DRP, dynamin-related protein; EF, embryonic fibroblast; ERR, estrogen-related receptor ; FA, fatty acid; GLUT, glucose transporter; IGF, insulin-like growth factor; IGF1R, IGF-1 receptor; IR, insulin receptor; KI, knock-in; KLF15, Krüppel-like factor 15 ; KO, knockout; L-CPT, CPT liver isoform; LCAD, long-chain acyl CoA dehydrogenase; MCAD, medium-chain acyl-CoA dehydrogenase; MCD, malonyl-CoA decarboxylase; MFN, mitofusin; NRF, nuclear respiratory factor; MPC, mitochondrial pyruvate carrier; OE, overexpression; OGA, O-GlcNAcase; OGT, O-GlcNAc Transferase; OPA, optic atrophy; PDK, pyruvate dehydrogenase kinase; PFK, phosphofructokinase; PGC,1 PPARγ co-activator 1; PI3K, phosphoinositide 3-kinase; POLGA, DNA polymerase gamma, subunit A; PP2Cm, protein phosphatase 2C , mitochondrial; PPAR, peroxisome proliferator-activated receptor; SCOT, succinyl-CoA:3-oxoacid-CoA transferase; SIRT, sirtuin; SLC, solute carrier family; STZ, streptozotocin; TFAm, mitochondrial transcription factor A; TFB1M, transcription factor B1; UCP, uncoupled protein; VLCAD, very long-chain acyl-CoA dehydrogenase; YME1L, ATP-dependent metalloprotease