Proceedings of The Physiological Society
AstraZeneca (2010) Proc Physiol Soc 18, C06 and PC06
Mildronate depletes carnitine in fast, intermediate and slow twitch rodent skeletal muscle
C. Porter1, D. Constantin-Teodosiu1, S. M. Gardiner1, B. Leighton2, S. M. Poucher2, P. L. Greenhaff1
1. School of Biomedical Sciences, University of Nottingham, Nottingham, United Kingdom. 2. Cardiovascular and Gastrointestinal Discovery Department, AstraZeneca Pharmaceuticals, Cheshire, United Kingdom.
Table 1. Muscle carnitine moieties in muscles of differing fibre compositions from Han Wistar rats following 10 days of oral mildronate supplementation.<\#13>
Values expressed as means ± S.E.M. (n=8). Concentrations are expressed as mmol.kg-1 of dry muscle. Mean values were compared using a Student’s unpaired t test. *, *** Significantly different from the corresponding control group (P<0.05; P<0.001, respectively).
Carnitine has two distinct metabolic roles in skeletal muscle: (i) in translocating long-chain fatty acids across the mitochondrial membranes for oxidation, and (ii) in maintaining a viable mitochondrial free coenzyme A pool (1). Mildronate administration has been shown to reduce heart and liver carnitine concentration by inhibiting carnitine biogenesis and accelerating its renal clearance (2). Given that >95% of the body’s carnitine store is located in skeletal muscle, the aim of this present study was to investigate the impact of oral mildronate administration on carnitine moieties in skeletal muscles of differing fibre composition. Sixteen male Wistar rats were randomly assigned to 2 groups that received either drinking water (control, n=8) or drinking water supplemented with mildronate (mildronate, n=8) for 10 days (1,600 mg.kg-1 on days 1-2 and 800 mg.kg-1 thereafter). After 10 days, the extensor digitorum longus (EDL), gastrocnemius (GAS), soleus (SOL) and tibialis anterior (TA) muscles, selected for their different fibre compositions, were excised under terminal anaesthesia (sodium pentobarbital, i.p. 120 mg.kg-1). Mildronate administration resulted in a marked reduction in total carnitine (sum of free and acyls) in all tissues (P<0.001), but the reduction in free carnitine was particularly remarkable (P<0.001, Table 1). This study has shown for the first time that mildronate depletes free and total carnitine in fast twitch, intermediate and slow twitch rodent skeletal muscle fibres. Furthermore, this present study has demonstrated that oral administration of mildronate provides an ideal model to investigate the significance of carnitine availability on metabolic regulation and physiological function in skeletal muscle in vivo.
Where applicable, experiments conform with Society ethical requirements