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Articles in PresS, published online ahead of print December 11, 2001
Am J Physiol Endocrinol Metab, 10.1152/ajpendo.00233.2001
Submitted on May 29, 2001
Accepted on December 6, 2001
1 Biochemsitry and Physiology, East Carolina University, Greenville, NC, USA
2 Medicine, Harvard University, Charlestown, MA, USA
3 Medicine, Duke University, Durham, NC, USA; Biochemsitry and Physiology, East Carolina University, Greenville, NC, USA
* To whom correspondence should be addressed. E-mail: muoio{at}duke.edu.
CPT1, which is expressed as two distinct isoforms in liver (
) and muscle (ß), catalyzes the rate-limiting step in the transport of fatty acid into the mitochondria. Malonyl-CoA, a potent inhibitor CPT1, is considered a key regulator of fatty acid oxidation in both tissues. Still unanswered is how muscle fatty acid oxidation proceeds despite malonyl-CoA concentrations that exceed the IC50 for CPT1ß. We evaluated malonyl-CoA suppressible [14C]palmitate oxidation and CPT1 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 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 CPT1 activity were greater in mitochondria from RG compared to WG. Ribonuclease protection assays were performed to evaluate whether our data might be explained by differential expression of CPT1 splice variants. We detected the presence of two CPT1ß splice variants that were more abundant in red compared to 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 CPT1 activity in red muscle, suggesting fiber-type specific expression of distinct CPT1 isoforms and/or post-translational modulations that have yet to be elucidated.
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