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. Meldonium (3-(2,2,2-trimethylhydrazinium)-propionate) inhibits carnitine synthesis and tissue uptake, although 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 meldonium-supplemented water (meldonium, n = 8) for 10 days [1.6 g kg body mass (BM) day days 1-2, 0.8 g kg BM day thereafter]. From days 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 days 7 to 10. Compared to control, meldonium 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 the control, whereas soleus and liver glycogen contents were less (P < 0.01 and P < 0.01, respectively). In a second study, male Wistar rats received water (n = 8) or meldonium-supplemented water (n = 8) as above, and kidney, heart and extensor digitorum longus muscle (EDL) and soleus muscles were collected. Compared to control, meldonium depleted total carnitine content (all P < 0.001), reduced carnitine transporter protein and glycogen content, and increased pyruvate dehydrogenase kinase 4 mRNA abundance in the heart, EDL and soleus. In total, 189 mRNAs regulating fuel selection were differentially expressed in soleus in meldonium 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.

Meldonium improves Huntington’s disease mitochondrial dysfunction by restoring peroxisome proliferator‐activated receptor γ coactivator 1α expression

“…Again, the effects observed were related to an increased expression of Spargel (srl) gene, the only orthologue of the PGC-1 family in Drosophila (Gershman et al, 2007). A recent study based on an RNAi approach reported that knocking down the Spargel gene reduced the locomotion ability of adult flies (Merzetti & Staveley, 2015), inducing time-dependent impairment in their climbing ability Regarding the meldonium effects that we described, we cannot relate them in an oversimplified way to the reported mechanism of action of the drug on endogenous carnitine synthesis and tissue uptake leading to a reduction of cytotoxic intermediate products of highlighting the regulation of discrete cellular functions and metabolic pathways (Porter et al, 2017).…”

The High Costs of Low-Grade Inflammation: Persistent Fatigue as a Consequence of Reduced Cellular-Energy Availability and Non-adaptive Energy Expenditure

“…L-carnitine is important for transport of fatty acids across the mitochondrial membrane for β-oxidation and adenosine triphosphate production. Thus, reductions in L-carnitine indicate reduced availability of fatty acids in the mitochondria and reduced tricarboxylic acid activity (Porter et al, 2017 ).…”

The Effects of Meldonium on the Renal Acute Ischemia/Reperfusion Injury in Rats

“…Meldonium inhibits gamma-butyrobetaine dioxygenase, the enzyme catalyzing the final step in the carnitine biosynthesis, and the carnitine palmitoyltransferase-1, an inner mitochondria membrane enzyme that catalyzes transfer of the acyl group from coenzyme-A to carnitine. As a result, long-chain fatty acids transport from cytosol into mitochondria is reduced and redirected to peroxisomes [7]. In peroxisomes, long-chain fatty acids are metabolized to medium- and short-chain acyl carnitines for further oxidation in mitochondria, which prevents the mitochondrial accumulation of toxic long-chain intermediates [8].…”