Table 1.

Models of altered substrate metabolism and implications for cardiac function

Pathway	Gene	Knock-out (KO) or Transgenic (TG)	Metabolism	Function (baseline)	Pathological hypertrophy	Reference
Glucose uptake	Glucose transporter 1	Cardiac specific TG	↑ glucose uptake ↑ glycolysis	Normal	Normal function	37, 38
					Similar hypertrophy as control
Glucose uptake	Glucose transporter 1	Cardiac specific KO	↓ glucose uptake ↓ glycolysis	Normal	Similar dysfunction/hypertrophy as control	40
			↑ FAO		Maintained FAO/glycolysis
Glucose uptake	Glucose transporter 4	Cardiac specific KO	↑ glucose uptake ↑ glycolysis	Compensated hypertrophy, normal function	–	41
Glucose utilization	Hexokinase II	Cardiac specific TG	↑ glycolysis	Normal	Normal function	42, 43
			↑ glycogen production		prevention of hypertrophy
Glucose oxidation	Pyruvate dehydrogenase kinase 4	Cardiac specific TG	↓ glucose oxidation	Normal	-	44
			↑ FAO
Lipid metabolism	Peroxisome proliferator-activated receptor alpha	Whole body KO	↓ FAO	Impaired (Cardiomyopathy)	-	62, 63
			↑ glucose oxidation
			Impaired energy generation
Lipid metabolism	Peroxisome proliferator-activated receptor alpha	Cardiac specific TG	↓ glucose oxidation	Impaired (Cardiac hypertrophy)	-	61
			↑ FAO
Lipid metabolism	Peroxisome proliferator-activated receptor β/γ	Cardiac specific KO	↓ FAO	Impaired (Cardiomyopathy)	-	64
			↑ glucose oxidation
			Lipid accumulation
Lipid metabolism	Peroxisome proliferator-activated receptor β/γ	Inducible cardiac specific TG	↑ oxidative metabolism (glucose + FA)	Normal	–	65
FA uptake	FAT/CD36	Inducible cardiac specific KO	Increased energetics	Normal	Worsened function and hypertrophy	66-68
			↓ FAO
			↑ glucose oxidation
FAO	Carnitine palmitoyltransferase 1b	Heterozygous whole body KO	↓ FAO	Normal	Worsened function and hypertrophy	69
			↑ glucose oxidation		Lipid accumulation
					Cardiomyocyte death
FAO	Acetyl-CoA carboxylase 2	Cardiac specific KO	↑ FAO	Normal	Normal function	75, 76
			↓ glucose oxidation		prevention of hypertrophy
Keton body metabolism	Succinyl-CoA:3-oxoacid-CoA transferase	Cardiac specific KO	Impaired ketone body oxidation	Normal	Worsened function and hypertrophy	91
			normal glucose/FA use
BCAA metabolism	Mitochondrial-targeted 2C-type protein phosphatase	Whole body KO	BCAA+BCKA accumulation	Normal	Accelerated heart failure	96-98
BCAA metabolism	mitochondrial branched-chain aminotransferase	Whole body KO	BCAA accumulation	Hypertrophy	–	93