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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. 2007 Dec 15; 43(12):1656-69.FR

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.

Authors+Show Affiliations

Department of Medical Biochemistry, Dr. AL Mudaliar Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai 600 113, India.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18037131

Citation

Tamilselvan, Jayavelu, et al. "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 Radical Biology & Medicine, vol. 43, no. 12, 2007, pp. 1656-69.
Tamilselvan J, Jayaraman G, Sivarajan K, et al. 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. 2007;43(12):1656-69.
Tamilselvan, J., Jayaraman, G., Sivarajan, K., & 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 Radical Biology & Medicine, 43(12), 1656-69.
Tamilselvan J, et al. 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. 2007 Dec 15;43(12):1656-69. PubMed PMID: 18037131.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Tamilselvan,Jayavelu, AU - Jayaraman,Gopalswamy, AU - Sivarajan,Kumarasamy, AU - Panneerselvam,Chinnakkannu, Y1 - 2007/09/14/ PY - 2007/07/11/received PY - 2007/08/26/revised PY - 2007/08/31/accepted PY - 2007/11/27/pubmed PY - 2008/2/12/medline PY - 2007/11/27/entrez SP - 1656 EP - 69 JF - Free radical biology & medicine JO - Free Radic Biol Med VL - 43 IS - 12 N2 - 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. SN - 0891-5849 UR - https://www.unboundmedicine.com/medline/citation/18037131/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0891-5849(07)00594-1 DB - PRIME DP - Unbound Medicine ER -