Proceedings of The Physiological Society
University of Oxford (2011) Proc Physiol Soc 23, PC96
Skeletal muscle carnitine depletion attenuates fat oxidation and increases carbohydrate oxidation in the rat.
C. Porter1, D. Constantin-Teodosiu1, B. Leighton2, S. M. Poucher2, P. L. Greenhaff1
1. School of Biomedical Sciences, University of Nottingham, Nottingham, United Kingdom. 2. CVGI Discovery iMED, AstraZeneca Pharmaceuticals, Macclesfield, United Kingdom.
Mildronate impairs carnitine biogenesis and accelerates its renal clearance, reducing plasma and tissue carnitine content1. Carnitine, as a principal substrate for carnitine palmitoyl transferase 1 (CPT 1), plays an obligatory role in skeletal muscle long chain fatty oxidation2. We hypothesised that pharmacologically lowering skeletal muscle carnitine content would attenuate whole body fatty acid oxidation whilst concomitantly increasing carbohydrate (CHO) oxidation in the rat. Sixteen, 10 week old male lean Zucker rats randomly received either water (CON, n=8) or mildronate supplemented water (MIL, n=8) for 10 days (1.6 g.kg-1 bm.d-1 for 2 days and 0.8 g.kg-1 bm.d-1 thereafter). On days 7 to 10 animals were housed in Oxymax indirect calorimetry chambers where O2 consumption and CO2 production were measured continuously and substrate oxidation rates calculated thereafter3. On day 10, the soleus muscle was excised from both hind limbs under terminal anaesthesia (sodium thiobutabarbital, 125 mg.kg-1 i.p. Inactin™, Sigma) and ‘snap’ frozen in liquid nitrogen. Significant differences between groups were detected using an unpaired Student’s t test. Compared with CON, soleus muscle carnitine content was 79% lower in the MIL group (4.92±0.12 vs. 1.02±0.05 mmol.kg-1 dm, [mean±SEM], P<0.001). During a 12 hour fast on day 10 lipid oxidation was 18% lower in the MIL group compared to CON (8052±128 vs. 6601±122 µmol.kg-1, P<0.001), while CHO oxidation was increased by 17% (4447±184 vs. 5211±214 µmol.kg-1 P<0.01). Skeletal muscle glycogen content was 72% lower in MIL compared to CON (30.0±7.4 vs. 8.5±2.9 mmol.kg-1 dm, P<0.05). These novel data demonstrate skeletal muscle carnitine depletion profoundly affects whole body fat and CHO oxidation in vivo in the rat. Carnitine depletion may therefore be a muscle orientated pharmacological approach to increase muscle CHO oxidation in insulin resistant states.
Where applicable, experiments conform with Society ethical requirements