PMID:18037131

Citation	Tamilselvan, J, Jayaraman, G, Sivarajan, K and Panneerselvam, C (2007) Age-dependent upregulation of p53 and cytochrome c release and susceptibility to apoptosis in skeletal muscle fiber of aged rats: role of carnitine and lipoic acid. Free Radic. Biol. Med. 43:1656-69
Abstract	Mitochondrial dysfunction has been implicated in the regulation of myofiber loss during aging, possibly by apoptotic pathways. However, the mitochondrial-mediated pathway of apoptosis by cytochrome c in skeletal muscle remains ambiguous. To understand this, we have studied the upstream and downstream events of cytochrome c release, and assessed the efficacy of carnitine and lipoic acid cosupplementation. The results show that elevated levels of cytosolic cytochrome c activate apoptosis in aged rats, and was confirmed further by in vitro caspase-3 assay. Interestingly, the exogenous addition of cytochrome c results in a much higher increase of caspase-3 activity in aged treated rats than age-matched control rats, strongly suggesting that cytochrome c is a limiting factor for caspase-3 activation in the cytosol. Carnitine and lipoic acid supplement decreased apoptosis in aged rats by maintaining mitochondrial membrane integrity and thereby preventing further loss of cytochrome c in vivo. Furthermore, the upregulation of p53 observed in aged rats is attributed to the loss of outer mitochondrial membrane integrity and subsequent release of cytochrome c through BH3-only proteins. In conclusion, the p53-dependent activation of the mitochondrial-cytochrome c pathway of apoptosis in the present study suggests the existence of cross talk between mitochondria and nucleus. However, the exact molecular mechanism remains to be explored. Oral supplements of carnitine and lipoic acid play an antiapoptotic role in aged rat skeletal muscle by protecting mitochondrial membrane integrity.
Links	PubMed Online version:10.1016/j.freeradbiomed.2007.08.028
Keywords	Aging/genetics; Aging/metabolism; Aging/pathology; Animals; Apoptosis/drug effects; Apoptotic Protease-Activating Factor 1/genetics; Base Sequence; Carnitine/pharmacology; Caspase 3/genetics; Caspase 3/metabolism; Caspase 9/genetics; Cytochromes c/metabolism; Cytochromes c/pharmacology; DNA Primers/genetics; Dietary Supplements; Free Radicals/metabolism; Genes, p53; Male; Muscle Fibers, Skeletal/drug effects; Muscle Fibers, Skeletal/metabolism; Muscle Fibers, Skeletal/pathology; Muscle, Skeletal/cytology; Muscle, Skeletal/drug effects; Muscle, Skeletal/metabolism; Proto-Oncogene Proteins c-bcl-2/metabolism; RNA, Messenger/genetics; RNA, Messenger/metabolism; Rats; Rats, Wistar; Thioctic Acid/pharmacology; Tumor Suppressor Protein p53/metabolism; Up-Regulation
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
RAT:P53	involved_in	GO:0007568: aging	ECO:0000270: expression pattern evidence used in manual assertion		P		Seeded From UniProt	complete

References

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