Table 1.

Experimental models of BTHS cardiomyopathy. Summary of the BTHS experimental models with cardiomyopathy phenotype, including Taz knockdown (KD)/knockout (KO) murine models, mouse embryonic stem cell (ESC)-derived cardiomyocytes, and human-induced pluripotent stem cell (iPSC)-derived cardiomyocytes. DOX: doxycycline; mo.: month.

Taz Knockdown Murine Models
DOX Induction	DOX Condition	Knockdown Efficiency	CL Abnormalities	Cardiac Mitochondrial Phenotype	Cardiac Function Phenotype
Gestation	625 mg/kg chow [54,55,56,57,58,59,60,61,62,63]	>90% mRNA reduction [54,55,57–59] >95% protein reduction [54,59]	Elevated MLCL and MLCL/CL ratio [54,55,57]. Decreased mature CL [57,59]. Total CL reduction [54,55,56,58,59,60].	Prior to cardiac dysfunction: increased mitochondrial number [54]; mitochondrial aggregation [54]; abnormal morphology (onion- and string-shaped mitochondria, abnormal cristae) [54,56]; decreased respiration capacity [57,58,59,61,64]; increased ROS [47,59]; decreased mitochondrial Ca2+ uptake [63].	Normal heart function at 2 and 5 mo. [55,56,57,59]. Dilated LV chamber and systolic dysfunction at 7–8 mo. [54].
	200 mg/kg chow [65,66]	~90% mRNA reduction [65]	Elevated MLCL [65]. Decreased mature CL [65].	Increased mitochondrial number [65,66]; mitochondrial aggregation [65,66]; giant or smaller mitochondria [66]; abnormal cristae [66]; decreased ETC complex I, II, or III activity at 2 and 5 mo. [66].	Systolic dysfunction at 5 [64,66] and 7 mo. [65].
	2 mg DOX/mL water [67]	70–80% mRNA reduction [67]	Elevated MLCL/CL ratio [67].	Decreased mitochondrial number [67]; giant or smaller mitochondria [67], and abnormal cristae at E13.5 [67]. Decreased mitochondrial density [67], vacuolated cristae [67], smaller mitochondria at newborn stage [67].	Prenatal and perinatal death [67]; Noncompaction cardiomyopathy [67]; and defective ventricular septation at E13.5 [67].
Adult age	625 mg/kg chow (2–4 mo.) [68]	80% mRNA reduction in the induction period [68]	Decreased mature CL [68].	Normal OXPHOS activity but increased ROS production at 4 mo. [68].	N/A
	2 mg/mL water (3–8 mo.) [67]	N/A	Elevated MLCL Decreased total CL [67].	N/A	N/A
Taz Knockout Murine Models
	Knockout Strategy	Knockout Efficiency	CL Abnormalities	Cardiac Mitochondria Phenotype	Cardiac Function Phenotype
Global knockout	Taz germline deletion [14].	Taz protein absence in heart tissue [14].	Elevated MLCL/CL ratio [14].	Mitochondrial aggregation [14]; increased mitochondrial number [14]; smaller mitochondria [14]; abnormal cristae [14].	20% of gKO mice survive postnatally [14]. Survivors displayed heart failure with cardiomyocyte apoptosis and cardiac fibrosis starting at 3 mo. [14].
Cardiac- specific knockout	Cardiomyocyte-specific Cre (Myh6-Cre [14,69] or Xmlc2-Cre) [15].	Taz protein decreased in heart tissue, isolated CM and isolated cardiac mitochondria [14,15].	Elevated MLCL and MLCL/CL ratio [14,15]; decreased total CL and mature CL [15]; increased nascent CL [15]; accumulated CL biosynthesis precursor [15].	Prior to cardiac dysfunction: increased mitochondrial number [15], smaller and longer mitochondria [15]; abnormal shapes (onion- and donut-shaped) [15], disorganized and hyperbranching cristae [15]; impaired mitochondrial respiration [15], elevated ROS [15,69].	cKO:Xmlc2-Cre: less than 5% lethality with significantly enlarged hearts, majority developed DCM at 4 mo. without cardiac fibrosis [15]. cKO:Myh6-Cre: cardiac dysfunction at 2 mo. [14]. Increased heart weight, CM apoptosis, and cardiac fibrosis at 6 mo. [14]; increased arrythmia vulnerability at 1.5 mo. [69].
Cultured Cardiomyocytes (CMs)
	Generation of iPSC	CL Abnormalities	Mitochondrial Phenotype		Function
ESCs derived CMs	TAZ KO [70]	Increased MLCL/CL ratio [70]; increased nascent CL [70]	Lost cristae parallel orientation and form branching lamellae cristae ratio [70]		N/A
iPSC derived CMs	BTHS patient-derived iPSC [57,71]; TAZ mutant by CRISPR-Cas9 mediated gene editing [71]	Increased MLCL/CL ratio and nascent CL [57,71]	Smaller mitochondria [71]; decreased respiratory capacity and ATP production [57,71]; elevated ROS [57,71].		Abnormal sarcomere structure [57,71]; decreased contractility [71].