JCI -
Long–echo time MR spectroscopy for skeletal muscle acetylcarnitine detection
JCI - Long–echo time MR spectroscopy for skeletal muscle acetylcarnitine detection Go to JCI Insight About Editors Consulting Editors For authors Publication ethics Alerts Advertising Job board Subscribe Contact Current issue Past issues By specialty Back COVID-19 Cardiology Gastroenterology Immunology Metabolism Nephrology Neuroscience Oncology Pulmonology Vascular biology All ... Videos BackVideos Conversations with Giants in Medicine Author's Takes Reviews BackReviews Reviews View all reviews ... Review Series Immune Environment in Glioblastoma (Upcoming) 25th Anniversary of the Korsmeyer Award collection (Nov 2022) Aging (Jul 2022) Next-Generation Sequencing in Medicine (Jun 2022) New Therapeutic Targets in Cardiovascular Diseases (Mar 2022) Immunometabolism (Jan 2022) Circadian Rhythm (Oct 2021) View all review series ... Viewpoint Collections Back In-Press Preview Commentaries Concise Communication Editorials Viewpoint Top read articles Clinical Medicine JCI This Month BackJCI This Month Current issue Past issues The Journal of Clinical Investigation Current issue Past issues Specialties Reviews Review series Videos Conversations with Giants in Medicine Author's Takes Collections In-Press Preview Commentaries Concise Communication Editorials Viewpoint Top read articles Journal Details About Editors Consulting Editors For authors Publication ethics Alerts Advertising Job board Subscribe Contact Top Tools View PDF Download citation information Send a comment Share this article Terms of use Standard abbreviations Need help? Email the journal AddThis Sharing ButtonsShare to FacebookFacebookShare to TwitterTwitterShare to PrintPrintShare to EmailEmailShare to MoreAddThis3 Go to Top Abstract Introduction Results Discussion Methods Supplemental material Acknowledgments Footnotes References Version history PDF Metrics See more details Tweeted by 2 91 readers on Mendeley 1 readers on CiteULike Article usage Citations to this article (44) Advertisement Technical AdvanceMetabolism Free access | 10.1172/JCI74830 Long–echo time MR spectroscopy for skeletal muscle acetylcarnitine detection Lucas Lindeboom,1,2,3 Christine I. Nabuurs,2,3,4 Joris Hoeks,1,3 Bram Brouwers,1,3 Esther Phielix,1,3 M. Eline Kooi,2,5 Matthijs K.C. Hesselink,3,4 Joachim E. Wildberger,2 Robert D. Stevens,6 Timothy Koves,6 Deborah M. Muoio,6 Patrick Schrauwen,1,3 and Vera B. Schrauwen-Hinderling1,2,3 1Department of Human Biology, 2Department of Radiology, 3NUTRIM School for Nutrition, Toxicology and Metabolism, 4Department of Human Movement Sciences, and 5CARIM School for Cardiovascular Diseases in Maastricht, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands. 6Department of Pharmacology and Cancer Biology, Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA. Address correspondence to: Patrick Schrauwen, Department of Human Biology, Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Phone: 31.0.43.388.1502; E-mail: [email protected]. Authorship note: Patrick Schrauwen and Vera B. Schrauwen-Hinderling contributed equally to this work. Find articles by Lindeboom, L. in: JCI | PubMed | Google Scholar 1Department of Human Biology, 2Department of Radiology, 3NUTRIM School for Nutrition, Toxicology and Metabolism, 4Department of Human Movement Sciences, and 5CARIM School for Cardiovascular Diseases in Maastricht, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands. 6Department of Pharmacology and Cancer Biology, Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA. Address correspondence to: Patrick Schrauwen, Department of Human Biology, Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Phone: 31.0.43.388.1502; E-mail: [email protected]. Authorship note: Patrick Schrauwen and Vera B. Schrauwen-Hinderling contributed equally to this work. Find articles by Nabuurs, C. in: JCI | PubMed | Google Scholar 1Department of Human Biology, 2Department of Radiology, 3NUTRIM School for Nutrition, Toxicology and Metabolism, 4Department of Human Movement Sciences, and 5CARIM School for Cardiovascular Diseases in Maastricht, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands. 6Department of Pharmacology and Cancer Biology, Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA. Address correspondence to: Patrick Schrauwen, Department of Human Biology, Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Phone: 31.0.43.388.1502; E-mail: [email protected]. Authorship note: Patrick Schrauwen and Vera B. Schrauwen-Hinderling contributed equally to this work. Find articles by Hoeks, J. in: JCI | PubMed | Google Scholar 1Department of Human Biology, 2Department of Radiology, 3NUTRIM School for Nutrition, Toxicology and Metabolism, 4Department of Human Movement Sciences, and 5CARIM School for Cardiovascular Diseases in Maastricht, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands. 6Department of Pharmacology and Cancer Biology, Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA. Address correspondence to: Patrick Schrauwen, Department of Human Biology, Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Phone: 31.0.43.388.1502; E-mail: [email protected]. Authorship note: Patrick Schrauwen and Vera B. Schrauwen-Hinderling contributed equally to this work. Find articles by Brouwers, B. in: JCI | PubMed | Google Scholar 1Department of Human Biology, 2Department of Radiology, 3NUTRIM School for Nutrition, Toxicology and Metabolism, 4Department of Human Movement Sciences, and 5CARIM School for Cardiovascular Diseases in Maastricht, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands. 6Department of Pharmacology and Cancer Biology, Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA. Address correspondence to: Patrick Schrauwen, Department of Human Biology, Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Phone: 31.0.43.388.1502; E-mail: [email protected]. Authorship note: Patrick Schrauwen and Vera B. Schrauwen-Hinderling contributed equally to this work. Find articles by Phielix, E. in: JCI | PubMed | Google Scholar 1Department of Human Biology, 2Department of Radiology, 3NUTRIM School for Nutrition, Toxicology and Metabolism, 4Department of Human Movement Sciences, and 5CARIM School for Cardiovascular Diseases in Maastricht, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands. 6Department of Pharmacology and Cancer Biology, Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA. Address correspondence to: Patrick Schrauwen, Department of Human Biology, Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Phone: 31.0.43.388.1502; E-mail: [email protected]. Authorship note: Patrick Schrauwen and Vera B. Schrauwen-Hinderling contributed equally to this work. Find articles by Kooi, M. in: JCI | PubMed | Google Scholar 1Department of Human Biology, 2Department of Radiology, 3NUTRIM School for Nutrition, Toxicology and Metabolism, 4Department of Human Movement Sciences, and 5CARIM School for Cardiovascular Diseases in Maastricht, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands. 6Department of Pharmacology and Cancer Biology, Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA. Address correspondence to: Patrick Schrauwen, Department of Human Biology, Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Phone: 31.0.43.388.1502; E-mail: [email protected]. Authorship note: Patrick Schrauwen and Vera B. Schrauwen-Hinderling contributed equally to this work. Find articles by Hesselink, M. in: JCI | PubMed | Google Scholar 1Department of Human Biology, 2Department of Radiology, 3NUTRIM School for Nutrition, Toxicology and Metabolism, 4Department of Human Movement Sciences, and 5CARIM School for Cardiovascular Diseases in Maastricht, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands. 6Department of Pharmacology and Cancer Biology, Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA. Address correspondence to: Patrick Schrauwen, Department of Human Biology, Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Phone: 31.0.43.388.1502; E-mail: [email protected]. Authorship note: Patrick Schrauwen and Vera B. Schrauwen-Hinderling contributed equally to this work. Find articles by Wildberger, J. in: JCI | PubMed | Google Scholar 1Department of Human Biology, 2Department of Radiology, 3NUTRIM School for Nutrition, Toxicology and Metabolism, 4Department of Human Movement Sciences, and 5CARIM School for Cardiovascular Diseases in Maastricht, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands. 6Department of Pharmacology and Cancer Biology, Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA. Address correspondence to: Patrick Schrauwen, Department of Human Biology, Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Phone: 31.0.43.388.1502; E-mail: [email protected]. Authorship note: Patrick Schrauwen and Vera B. Schrauwen-Hinderling contributed equally to this work. Find articles by Stevens, R. in: JCI | PubMed | Google Scholar 1Department of Human Biology, 2Department of Radiology, 3NUTRIM School for Nutrition, Toxicology and Metabolism, 4Department of Human Movement Sciences, and 5CARIM School for Cardiovascular Diseases in Maastricht, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands. 6Department of Pharmacology and Cancer Biology, Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA. Address correspondence to: Patrick Schrauwen, Department of Human Biology, Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Phone: 31.0.43.388.1502; E-mail: [email protected]. Authorship note: Patrick Schrauwen and Vera B. Schrauwen-Hinderling contributed equally to this work. Find articles by Koves, T. in: JCI | PubMed | Google Scholar 1Department of Human Biology, 2Department of Radiology, 3NUTRIM School for Nutrition, Toxicology and Metabolism, 4Department of Human Movement Sciences, and 5CARIM School for Cardiovascular Diseases in Maastricht, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands. 6Department of Pharmacology and Cancer Biology, Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA. Address correspondence to: Patrick Schrauwen, Department of Human Biology, Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Phone: 31.0.43.388.1502; E-mail: [email protected]. Authorship note: Patrick Schrauwen and Vera B. Schrauwen-Hinderling contributed equally to this work. Find articles by Muoio, D. in: JCI | PubMed | Google Scholar 1Department of Human Biology, 2Department of Radiology, 3NUTRIM School for Nutrition, Toxicology and Metabolism, 4Department of Human Movement Sciences, and 5CARIM School for Cardiovascular Diseases in Maastricht, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands. 6Department of Pharmacology and Cancer Biology, Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA. Address correspondence to: Patrick Schrauwen, Department of Human Biology, Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Phone: 31.0.43.388.1502; E-mail: [email protected]. Authorship note: Patrick Schrauwen and Vera B. Schrauwen-Hinderling contributed equally to this work. Find articles by Schrauwen, P. in: JCI | PubMed | Google Scholar 1Department of Human Biology, 2Department of Radiology, 3NUTRIM School for Nutrition, Toxicology and Metabolism, 4Department of Human Movement Sciences, and 5CARIM School for Cardiovascular Diseases in Maastricht, Maastricht University Medical Center (MUMC+), Maastricht, The Netherlands. 6Department of Pharmacology and Cancer Biology, Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA. Address correspondence to: Patrick Schrauwen, Department of Human Biology, Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Phone: 31.0.43.388.1502; E-mail: [email protected]. Authorship note: Patrick Schrauwen and Vera B. Schrauwen-Hinderling contributed equally to this work. Find articles by Schrauwen-Hinderling, V. in: JCI | PubMed | Google Scholar Authorship note: Patrick Schrauwen and Vera B. Schrauwen-Hinderling contributed equally to this work. Published October 1, 2014 - More info Published in Volume 124, Issue 11 on November 3, 2014 J Clin Invest. 2014;124(11):4915–4925. https://doi.org/10.1172/JCI74830. Copyright © 2014, American Society for Clinical Investigation Published October 1, 2014 - Version history Received: December 18, 2013; Accepted: August 28, 2014 View PDF AbstractAnimal models suggest that acetylcarnitine production is essential for maintaining metabolic flexibility and insulin sensitivity. Because current methods to detect acetylcarnitine involve biopsy of the tissue of interest, noninvasive alternatives to measure acetylcarnitine concentrations could facilitate our understanding of its physiological relevance in humans. Here, we investigated the use of long–echo time (TE) proton magnetic resonance spectroscopy (1H-MRS) to measure skeletal muscle acetylcarnitine concentrations on a clinical 3T scanner. We applied long-TE 1H-MRS to measure acetylcarnitine in endurance-trained athletes, lean and obese sedentary subjects, and type 2 diabetes mellitus (T2DM) patients to cover a wide spectrum in insulin sensitivity. A long-TE 1H-MRS protocol was implemented for successful detection of skeletal muscle acetylcarnitine in these individuals. There were pronounced differences in insulin sensitivity, as measured by hyperinsulinemic-euglycemic clamp, and skeletal muscle mitochondrial function, as measured by phosphorus-MRS (31P-MRS), across groups. Insulin sensitivity and mitochondrial function were highest in trained athletes and lowest in T2DM patients. Skeletal muscle acetylcarnitine concentration showed a reciprocal distribution, with mean acetylcarnitine concentration correlating with mean insulin sensitivity in each group. These results demonstrate that measuring acetylcarnitine concentrations with 1H-MRS is feasible on clinical MR scanners and support the hypothesis that T2DM patients are characterized by a decreased formation of acetylcarnitine, possibly underlying decreased insulin sensitivity. Introduction The use of proton magnetic resonance spectroscopy (1H-MRS) in human skeletal muscle has been instrumental in establishing the importance of ectopic fat accumulation in the development of type 2 diabetes mellitus (T2DM). It was found in a large number of studies that intramyocellular lipid (IMCL) levels are inversely related to insulin sensitivity (1, 2). However, the same methodology also resulted in the identification of the so-called athletes’ paradox: endurance-trained athletes are, despite being very insulin sensitive, also characterized by high IMCL levels (3). These findings have led to the development of new hypotheses to explain the relation between fat accumulation in muscle and insulin sensitivity. One of the interesting and novel hypotheses suggests a role for carnitine metabolism (4, 5). It has long been known that carnitine permits mitochondrial import of long-chain fatty acids for subsequent β-oxidation (6). However, it has recently been suggested that carnitine may also play a crucial regulatory role in substrate switching and glucose homeostasis (4, 5, 7). Acetylcarnitine is formed in conditions in which acetyl-CoA formation, either as end product of glycolysis or β-oxidation, exceeds its entry into the tricarboxylic (TCA) cycle. Free carnitine can act as a sink for excess acetyl groups in a reversible reaction catalyzed by the enzyme carnitine acetyltransferase (CRAT) (7). Acetylcarnitine, like other acylcarnitine esters, can readily be exported out of the mitochondria (Figure 1). Figure 1 Formation of acetylcarnitine. When acetyl-CoA formation exceeds use by the TCA cycle, carnitine can function as a sink for excess acetyl groups inside the mitochondria, thereby forming acetylcarnitine. This reversible reaction is catalyzed by the enzyme CRAT and leads to the release of free CoA. The formation of acetylcarnitine can help to keep the mitochondrial acetyl-CoA/free CoA ratio low, which is essential to sustaining TCA cycle flux and PDH activity. Acetylcarnitine can be transformed back to acetyl-CoA or can be exported outside the mitochondria. The protons contributing to the resonance of acetylcarnitine at 2.13 ppm in 1H-MRS are highlighted in the molecule structure. CPT1, carnitine palmitoyltransferase 1; FFA, free fatty acids; LCFA, long-chain fatty acids. The formation of acetylcarnitine helps to keep the mitochondrial acetyl-CoA/free CoA ratio low. A low acetyl-CoA/free CoA ratio is needed to maintain pyruvate dehydrogenation (PDH) activity (8), which is known to control the rate of aerobic carbohydrate oxidation. A compromised capacity to generate acetylcarnitine, either due to reduced CRAT activity or low carnitine concentrations, may reduce PDH activity, hence reducing oxidative degradation of glucose, a major concern in insulin-resistant muscle. Compromised mitochondrial entrance of pyruvate is reflected in decreased metabolic flexibility, an early detectable feature of insulin-resistant muscle. Indeed, Crat-knockout mice, which are unable to convert acetyl-CoA to acetylcarnitine, are characterized by decreased glucose tolerance. On the other hand, gain-of-function experiments of CRAT in primary human myotubes showed increased acetylcarnitine efflux and higher PDH activity (5). Similarly, a reduced availability of free carnitine caused by high-fat overfeeding hampered acetylcarnitine formation in rats, and carnitine supplementation was able to reverse diet-induced mitochondrial dysregulation, including restoration of PDH activity. Furthermore, acetylcarnitine formation was increased with increased levels of free carnitine in skeletal muscle of rats and in primary human skeletal myotubes (4). To test the relevance of acetylcarnitine in insulin resistance and T2DM in humans, it is key to measure acetylcarnitine levels in tissue. Acetylcarnitine has previously been visualized noninvasively using short–echo time (TE) 1H-MRS by subtracting pre- and postexercise spectra. Because the peak was not visible in the rest spectrum, only an exercise-induced difference signal could be quantified at 2.13 ppm (9). More recently, the observation of an alter… truncated (53,479 more characters in archive)