Table 1.

Temporal sequence of events induced by unloading/inactivity in rodent hindlimb muscles before the appearance of myofiber atrophy.

Time	Localization	Event	Consequences	Reference
6 h	costamere	loss of melusin	increased FoxO3-independent transcription of MAFbx-Atrogin-1	[128]
		redistribution of non-muscle α-actinin and β- and γ- actin	subsarcolemmal cytoskeleton reorganization	[229,230]
		loss of active sarcolemmal nNOS	FoxO3 nuclear translocation	[30]
		decreased sarcolemmal NO production	AMPK inactivity	[20]
	sarcoplasm	increased accumulation of active/uncoupled nNOS	increased NO/ROS production	[30]
	mitochondria	ROS production	loss of active sarcolemmal nNOS	[30]
		ROS production	covalent S-S tropomyosin species	[30]
	sarcolemma	loss of cholesterol	membrane instability loss of Na/K pump activity	[210,231]
		inhibition of 2subunit of Na/K pump	membrane instability	[231]
	nucleus	increased FoxO3 localization	transcriptional activity	[30]
		decreased nNOS transcription	decreased nNOS protein	[30]
12 h	sarcoplasm	AMPK inactivity	p70S6K activation loss of Na/K pump activity	[20,211]
		ceramide accumulation	sarcolemma instability	[210]
		increased phospo-p70S6K	pSer-IRS-1	[20,31]
24 h	sarcolemma/costamere	decreased levels of IRS-1	impaired Akt activation	[31]
		decreased integrin signaling activation	impaired Akt, ERK1/2 activation	[31,128]
	nucleus	increased FoxO3 transcription	increased protein levels and atrogene upregulation	[31,68,128,227]
		myosin gene down-regulation	fiber type transition	[2]
		multiple transcriptional changes	phenotype change	[68]
	sarcoplasm/nucleus	increased p53 protein levels	MuRF-1 and p21 upregulation	[57]
48 h	SR/ER	decreased Grp94/gp96 levels	decreased nNOS delivery to sarcolemma	[30]
	sarcoplasm	increased protein ubiquitination and deacetylation by HDAC1	increased protein catabolism, FoxO3 activation	[32,227]
		increased Bax/Bcl2 ratio; mitochondrial release of AIF; caspase -3 and caspase-8 activation	increased myonuclei apoptosis	[73]
		reduced myofiber cross-sectional area	earliest morphological evidence of muscle atrophy	[30]