Animal 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.
Lucas Lindeboom, Christine I. Nabuurs, Joris Hoeks, Bram Brouwers, Esther Phielix, M. Eline Kooi, Matthijs K.C. Hesselink, Joachim E. Wildberger, Robert D. Stevens, Timothy Koves, Deborah M. Muoio, Patrick Schrauwen, Vera B. Schrauwen-Hinderling
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.