HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: 291/6/E1341    most recent 00095.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Turpin, S. M. Articles by Watt, M. J. Search for Related Content PubMed PubMed Citation Articles by Turpin, S. M. Articles by Watt, M. J.

Apoptosis in skeletal muscle myotubes is induced by ceramides and is positively related to insulin resistance

¹St. Vincent's Institute of Medical Research and the Department of Medicine, The University of Melbourne, Fitzroy, Victoria; and ²Cellular and Molecular Metabolism Laboratory, School of Medical Sciences, Royal Melbourne Institute of Technology University, Bundoora, Victoria, Australia

Submitted 27 February 2006 ; accepted in final form 10 July 2006

Fatty acid-induced apoptosis occurs in pancreatic -cells and contributes to the metabolic syndrome. Skeletal muscle insulin resistance is mediated by fatty acid oversupply, which also contributes to the metabolic syndrome. Therefore, we examined whether fatty acids induce apoptosis in skeletal muscle myotubes, the proapoptotic signaling involved, and the effects on insulin sensitivity. Exposure of L6 myotubes to palmitate induced apoptosis, as demonstrated by increased caspase-3 activation, phosphatidylserine exposure on the plasma membrane, and terminal deoxynucleotide transferase dUTP nick end labeling and DNA laddering, both markers of DNA fragmentation. Ceramide content was concomitantly increased, indicating a potential role for ceramides in palmitate-induced apoptosis. Supporting this notion, reducing stearoyl-CoA desaturase-1 (SCD-1) protein content with short interfering RNA resulted in ceramide accumulation and was associated with increased apoptosis in the absence of palmitate. Furthermore, the membrane-permeable C₂-ceramide enhanced apoptosis in myotubes, whereas the ceramide synthase inhibitor, fumonisin B₁, abrogated the proapoptotic effects of palmitate. Insulin-stimulated glucose uptake was inhibited by palmitate treatment, whereas the addition of effector caspase inhibitors [Ac-DEVD-aldehyde (DEVD-CHO), Z-DQMD-FMK] independently restored >80% of the insulin-stimulated glucose uptake. These effects were observed independently from changes in the protein content of insulin signaling proteins, suggesting that proteosomal degradation is not involved in this process. We conclude that lipoapoptosis occurs in skeletal muscle myotubes, at least partially via de novo ceramide accumulation, and that inhibiting downstream apoptotic signaling improves glucose uptake in vitro.

lipoapoptosis; caspase 3; proteolysis; glucose uptake

This article has been cited by other articles:

				H. Sell, K. Eckardt, A. Taube, D. Tews, M. Gurgui, G. Van Echten-Deckert, and J. Eckel Skeletal muscle insulin resistance induced by adipocyte-conditioned medium: underlying mechanisms and reversibility Am J Physiol Endocrinol Metab, June 1, 2008; 294(6): E1070 - E1077. [Abstract] [Full Text] [PDF]

				E. D. Abel, S. E. Litwin, and G. Sweeney Cardiac Remodeling in Obesity Physiol Rev, April 1, 2008; 88(2): 389 - 419. [Abstract] [Full Text] [PDF]

				K. R. Underwood, W. J. Means, and M. Du Caspase 3 is not likely involved in the postmortem tenderization of beef muscle J Anim Sci, April 1, 2008; 86(4): 960 - 966. [Abstract] [Full Text] [PDF]

				C. Moro, S. Bajpeyi, and S. R. Smith Determinants of intramyocellular triglyceride turnover: implications for insulin sensitivity Am J Physiol Endocrinol Metab, February 1, 2008; 294(2): E203 - E213. [Abstract] [Full Text] [PDF]