Muscle carnitine availability plays a central role in regulating fuel metabolism in the rodent

Abstract

The body carnitine pool is primarily confined to skeletal muscle, where it regulates carbohydrate (CHO) and fat usage. Mildronate (3-(2,2,2-trimethylhydrazinium)-propionate) inhibits carnitine synthesis and tissue uptake, but the impact of carnitine depletion on whole-body fuel selection, muscle fuel metabolism and its molecular regulation is under-investigated. Male lean Zucker rats received water (control, n = 8) or mildronate-supplemented water (mildronate, n = 8) for 10 days (1.6 g kg⁻¹ body mass (bm)^.day⁻¹ day 1–2, 0.8 g kg⁻¹ bm day⁻¹ thereafter). From day 7–10, animals were housed in indirect calorimetry chambers after which soleus muscle and liver were harvested. Food and fluid intake, weight gain and physical activity levels were similar between groups from day 7–10. Compared to control, mildronate depleted muscle total carnitine (P < 0.001) and all carnitine esters. Furthermore, whole-body fat oxidation was less (P < 0.001) and CHO oxidation was greater (P < 0.05) compared to control, whilst soleus and liver glycogen content were less (P < 0.01 and P < 0.01, respectively). In a second study, male Wistar rats received water (n = 8) or mildronate-supplemented water (n = 8) as above, and kidney, heart, and EDL and soleus muscles were collected. Compared to control, mildronate depleted total carnitine content (all P < 0.001), reduced carnitine transporter protein and glycogen content, and increased PDK4 mRNA abundance in heart, EDL, and soleus. 189 mRNAs regulating fuel selection were differentially expressed in soleus in mildronate vs. control, and a number of cellular functions and pathways strongly associated with carnitine depletion were identified. Collectively, these data firmly support the premise that muscle carnitine availability is a primary regulator of fuel selection in vivo.

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