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Am J Physiol Endocrinol Metab 282: E1014-E1022, 2002. First published December 11, 2001; doi:10.1152/ajpendo.00233.2001
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Vol. 282, Issue 5, E1014-E1022, May 2002

Evidence of a malonyl-CoA-insensitive carnitine palmitoyltransferase I activity in red skeletal muscle

Jong-Yeon Kim1,*, Timothy R. Koves1,*, Geng-Sheng Yu3, Tod Gulick3, Ronald N. Cortright1, G. Lynis Dohm1, and Deborah M. Muoio1,2,*

1 Departments of Biochemistry and Physiology, East Carolina University, Greenville 27858; 2 Department of Medicine, Duke University Medical School, Durham, North Carolina 27710; and 3 Diabetes Research Laboratory, Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Charlestown, Massachusetts 02129

Carnitine palmitoyltransferase I (CPT I), which is expressed as two distinct isoforms in liver (alpha ) and muscle (beta ), catalyzes the rate-limiting step in the transport of fatty acid into the mitochondria. Malonyl-CoA, a potent inhibitor of CPT I, is considered a key regulator of fatty acid oxidation in both tissues. Still unanswered is how muscle beta -oxidation proceeds despite malonyl-CoA concentrations that exceed the IC50 for CPT Ibeta . We evaluated malonyl-CoA-suppressible [14C]palmitate oxidation and CPT I activity in homogenates of red (RG) and white (WG) gastrocnemius, soleus (SOL), and extensor digitorum longus (EDL) muscles. Adding 10 µM malonyl-CoA inhibited palmitate oxidation by 29, 39, 60, and 89% in RG, SOL, EDL, and WG, respectively. Thus malonyl-CoA resistance, which correlated strongly (0.678) with absolute oxidation rates (RG > SOL > EDL > WG), was greater in red than in white muscles. Similarly, malonyl-CoA-resistant palmitate oxidation and CPT I activity were greater in mitochondria from RG compared with WG. Ribonuclease protection assays were performed to evaluate whether our data might be explained by differential expression of CPT I splice variants. We detected the presence of two CPT Ibeta splice variants that were more abundant in red compared with white muscle, but the relative expression of the two mRNA species was unrelated to malonyl-CoA resistance. These results provide evidence of a malonyl-CoA-insensitive CPT I activity in red muscle, suggesting fiber type-specific expression of distinct CPT I isoforms and/or posttranslational modulations that have yet to be elucidated.

fatty acid oxidation; fiber-type specificity

* These authors contributed equally to the study.




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