Table 3.

Knockout and knock-in models of IGF1-Akt pathway components: effect on growth

Genotype1	Viability	Growth phenotype	References
Igf1 null	Severe neonatal lethality	Severe growth retardation	[37-39]
Igf1 null in muscle (Mef2c-Cre)	Viable	Normal growth	[63]
Igf1 receptor null	Severe neonatal lethality	Severe growth retardation	[37,39]
Igf1 receptor null in muscle (Mef2c-Cre)	Viable	Reduced body weight, reduced muscle fiber number and size	[63]
IRS1 null	Viable	Reduced growth (weight 30-60% of control)	[64,122]
IRS2 null	Viable	Almost normal growth (birth weight 90% of control)	[65]
PI3K p85α + p55α + p50α null	Perinatal lethality		[66]
PI3K p85α + p55α + p50α null in heart & muscle (MCK-Cre)	Viable	Normal growth	[68]
PI3K p85β null	Viable	Normal growth	[67]
PI3K p85α + p55α + p50α null in heart & muscle (MCK-Cre) and p85β null	Viable	Reduced heart size but not muscle size	[68]
PTEN null in heart & muscle (MCK-Cre)	Viable	Cardiac hypertrophy but normal skeletal muscle growth; unaffected overload-induced muscle hypertrophy; improved muscle regeneration	[70,71,123]
PDK1 null	Embryonic lethality		[124]
PDK1 knock-in mutant unable to bind phosphoinositides	Viable	Reduced growth (weight 35% of control)	[125]
PDK1 null in heart & muscle (MCK-Cre)	Lethal at 5-11 weeks	Dilated cardiomyopathy but no change in muscle	[73]
Akt1 null	Viable but shorter life span	Mild growth retardation (weight 80% of control)	[74,75]
Akt2 null	Viable	Normal growth	[76]
Akt1+Akt2 null	Neonatal lethality	Severe growth retardation (birth weight 50% of control), marked muscle atrophy	[77]
TSC1 null	Embryonic lethality		[126]
TSC2 null	Embryonic lethality		[127]
mTOR null	Embryonic lethality		[128,129]
mTOR null in muscle (HSA-Cre)	Viable but premature death	Reduced postnatal growth due to reduced fast muscle growth, severe myopathy	[88]
Raptor null	Embryonic lethality		[6]
Raptor null in muscle (HSA-Cre)	Viable	Normal growth	[87]
Rictor null in muscle (HSA-Cre)	Viable	Reduced postnatal growth with severe myopathy and premature death	[87]
S6K1 null	Viable	Reduced growth (birth weight 80% of control), reduced muscle growth (fiber size 80% of control in adult mice)	[89,117]
S6K2 null	Viable	Normal growth	[130]
S6K1+S6K2 null	Perinatal lethality	Reduced growth	[130]
4EBP1+4EBP2 null	Viable	Normal growth	[131]
FoxO1 null	Embryonic lethality		[132,133]
FoxO1 null in muscle (HSA-Cre)	Viable	Normal growth, slow to fast switch in muscle	[134,135]
FoxO3 null	Viable but female sterility	Normal growth	[133,36]
FoxO4 null	Viable	Normal growth	[137]
FoxO3+FoxO4 null	Viable	Normal growth	[137]
MAFbx null	Viable	Reduced muscle atrophy after denervation	[92]
Murf1 null	Viable	Reduced muscle atrophy after denervation	[92]

¹ Promoters used to drive Cre recombinase expression: HSA = human skeletal actin; MCK = muscle creatine kinase; Mef2c = a promoter that lies 71 kb upstream of the first translated exon of the Mef2c gene and is sufficient to direct expression exclusively to skeletal muscle from embryonic day 8.5.