Total body skeletal muscle mass: estimation by creatine (methyl-d3) dilution in humans.
Current methods for clinical estimation of total body skeletal muscle mass have significant limitations. We tested the hypothesis that creatine (methyl-d3) dilution (D3-creatine) measured by enrichment of urine D3-creatinine reveals total body creatine pool size, providing an accurate estimate of total body skeletal muscle mass. Healthy subjects with different muscle masses [n = 35: 20 men (19-30 yr, 70-84 yr), 15 postmenopausal women (51-62 yr, 70-84 yr)] were housed for 5 days. Optimal tracer dose was explored with single oral doses of 30, 60, or 100 mg D3-creatine given on day 1. Serial plasma samples were collected for D3-creatine pharmacokinetics. All urine was collected through day 5. Creatine and creatinine (deuterated and unlabeled) were measured by liquid chromatography mass spectrometry. Total body creatine pool size and muscle mass were calculated from D3-creatinine enrichment in urine. Muscle mass was also measured by magnetic resonance imaging (MRI), dual-energy x-ray absorptiometry (DXA), and traditional 24-h urine creatinine. D3-creatine was rapidly absorbed and cleared with variable urinary excretion. Isotopic steady-state of D3-creatinine enrichment in the urine was achieved by 30.7 ± 11.2 h. Mean steady-state enrichment in urine provided muscle mass estimates that correlated well with MRI estimates for all subjects (r = 0.868, P < 0.0001), with less bias compared with lean body mass assessment by DXA, which overestimated muscle mass compared with MRI. The dilution of an oral D3-creatine dose determined by urine D3-creatinine enrichment provides an estimate of total body muscle mass strongly correlated with estimates from serial MRI with less bias than total lean body mass assessment by DXA.
Muscle Metabolism Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline R&D, Research Triangle Park, North Carolina; Richard.V.Clark@GSK.com.
Richard V
RV
Clark
Muscle Metabolism Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline R&D, Research Triangle Park, North Carolina;
Ann C
AC
Walker
Muscle Metabolism Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline R&D, Research Triangle Park, North Carolina;
Robin L
RL
O'Connor-Semmes
Muscle Metabolism Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline R&D, Research Triangle Park, North Carolina;
Michael S
MS
Leonard
Muscle Metabolism Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline R&D, Research Triangle Park, North Carolina;
Ram R
RR
Miller
Muscle Metabolism Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline R&D, Research Triangle Park, North Carolina;
Stephen A
SA
Stimpson
KineMed Inc., Emeryville, California;
Scott M
SM
Turner
Pennington Biomedical Research Center, Baton Rouge, Louisiana; and.
Eric
E
Ravussin
Pennington Biomedical Research Center, Baton Rouge, Louisiana; and.
William T
WT
Cefalu
Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California.
Marc K
MK
Hellerstein
KineMed Inc., Emeryville, California;
William J
WJ
Evans
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001823:Body Composition / Q000502:physiology*; D002853:Chromatography, Liquid / Q000379:methods; D003401:Creatine / Q000097:blood* / Q000378:metabolism*; D003404:Creatinine / Q000652:urine; D005260:Female; D006801:Humans; D007201:Indicator Dilution Techniques; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000502:physiology*
D003404:Creatinine; D003401:Creatine
creatine; creatinine; lean body mass; muscle mass