PMID- 28605113 OWN - NLM STAT- MEDLINE DCOM- 20180205 LR - 20220129 IS - 1469-7793 (Electronic) IS - 0022-3751 (Print) IS - 0022-3751 (Linking) VI - 595 IP - 17 DP - 2017 Sep 1 TI - Muscle carnitine availability plays a central role in regulating fuel metabolism in the rodent. PG - 5765-5780 LID - 10.1113/JP274415 [doi] AB - KEY POINTS: Meldonium inhibits endogenous carnitine synthesis and tissue uptake, and accelerates urinary carnitine excretion, although the impact of meldonium-mediated muscle carnitine depletion on whole-body fuel selection, and muscle fuel metabolism and its molecular regulation is under-investigated. Ten days of oral meldonium administration did not impact on food or fluid intake, physical activity levels or body weight gain in the rat, whereas it depleted muscle carnitine content (all moieties), increased whole-body carbohydrate oxidation and muscle and liver glycogen utilization, and reduced whole-body fat oxidation. Meldonium reduced carnitine transporter protein expression across muscles of different contractile and metabolic phenotypes. A TaqMan PCR low-density array card approach revealed the abundance of 189 mRNAs regulating fuel selection was altered in soleus muscle by meldonium, highlighting the modulation of discrete cellular functions and metabolic pathways. These novel findings strongly support the premise that muscle carnitine availability is a primary regulator of fuel selection in vivo. 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(-1) body mass (BM) day(-1) days 1-2, 0.8 g kg(-1) BM day(-1) 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. CI - (c) 2017 The University of Nottingham. The Journal of Physiology (c) 2017 The Physiological Society. FAU - Porter, Craig AU - Porter C AD - MRC/ARUK Centre for Musculoskeletal Ageing Research, School of Life Sciences, University of Nottingham Medical School, Nottingham, UK. FAU - Constantin-Teodosiu, Dumitru AU - Constantin-Teodosiu D AUID- ORCID: 0000-0002-8448-5564 AD - MRC/ARUK Centre for Musculoskeletal Ageing Research, School of Life Sciences, University of Nottingham Medical School, Nottingham, UK. FAU - Constantin, Despina AU - Constantin D AD - MRC/ARUK Centre for Musculoskeletal Ageing Research, School of Life Sciences, University of Nottingham Medical School, Nottingham, UK. FAU - Leighton, Brendan AU - Leighton B AD - CVGI Discovery iMED, AstraZeneca, Macclesfield, UK. FAU - Poucher, Simon M AU - Poucher SM AD - CVGI Discovery iMED, AstraZeneca, Macclesfield, UK. FAU - Greenhaff, Paul L AU - Greenhaff PL AD - MRC/ARUK Centre for Musculoskeletal Ageing Research, School of Life Sciences, University of Nottingham Medical School, Nottingham, UK. LA - eng GR - MR/K00414X/1/MRC_/Medical Research Council/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20170716 PL - England TA - J Physiol JT - The Journal of physiology JID - 0266262 RN - 0 (Methylhydrazines) RN - 0 (RNA, Messenger) RN - 0 (Slc22a5 protein, rat) RN - 0 (Solute Carrier Family 22 Member 5) RN - 73H7UDN6EC (3-(2,2,2-trimethylhydrazine)propionate) RN - 9005-79-2 (Glycogen) RN - S7UI8SM58A (Carnitine) SB - IM CIN - J Physiol. 2017 Sep 1;595(17):5727-5728. PMID: 28733980 MH - Animals MH - Carnitine/*metabolism MH - Energy Metabolism/drug effects MH - Glycogen/metabolism MH - Liver/drug effects/metabolism MH - Male MH - Methylhydrazines/*pharmacology MH - Motor Activity/drug effects MH - Muscle, Skeletal/*drug effects/metabolism MH - Myocardium/metabolism MH - RNA, Messenger/metabolism MH - Rats, Wistar MH - Rats, Zucker MH - Solute Carrier Family 22 Member 5/metabolism PMC - PMC5577538 OTO - NOTNLM OT - carnitine OT - fat and carbohydrate metabolism OT - muscle fuel selection EDAT- 2017/06/13 06:00 MHDA- 2018/02/06 06:00 PMCR- 2018/09/01 CRDT- 2017/06/13 06:00 PHST- 2017/03/29 00:00 [received] PHST- 2017/05/31 00:00 [accepted] PHST- 2017/06/13 06:00 [pubmed] PHST- 2018/02/06 06:00 [medline] PHST- 2017/06/13 06:00 [entrez] PHST- 2018/09/01 00:00 [pmc-release] AID - TJP12470 [pii] AID - 10.1113/JP274415 [doi] PST - ppublish SO - J Physiol. 2017 Sep 1;595(17):5765-5780. doi: 10.1113/JP274415. Epub 2017 Jul 16.