(31)P MR Spectroscopy and Computational Modeling Identify a Direct Relation between Pi Content of an Alkaline Compartment in Resting Muscle and Phosphocreatine Resynthesis Kinetics in Active Muscle in Humans

The assessment of mitochondrial properties in skeletal muscle is important in clinical research, for instance in the study of diabetes. The gold standard to measure mitochondrial capacity non-invasively is the phosphocreatine (PCr) recovery rate after exercise, measured by (31)P Magnetic Resonance spectroscopy ((31)P MRS). Here, we sought to expand the evidence base for an alternative method to assess mitochondrial properties which uses (31)P MRS measurement of the Pi content of an alkaline compartment attributed to mitochondria (Pi(2); as opposed to cytosolic Pi (Pi(1))) in resting muscle at high magnetic field. Specifically, the PCr recovery rate in human quadriceps muscle was compared with the signal intensity of the Pi(2) peak in subjects with varying mitochondrial content of the quadriceps muscle as a result of athletic training, and the results were entered into a mechanistic computational model of mitochondrial metabolism in muscle to test if the empirical relation between Pi(2)/Pi(1) ratio and the PCr recovery was consistent with theory. Localized (31)P spectra were obtained at 7T from resting vastus lateralis muscle to measure the intensity of the Pi(2) peak. In the endurance trained athletes a Pi(2)/Pi(1) ratio of 0.07 ± 0.01 was found, compared to a significantly lower (p<0.05) Pi(2)/Pi(1) ratio of 0.03 ± 0.01 in the normally active group. Next, PCr recovery kinetics after in magnet bicycle exercise were measured at 1.5T. For the endurance trained athletes, a time constant τ(PCr) 12 ± 3 s was found, compared to 24 ± 5s in normally active subjects. Without any parameter optimization the computational model prediction matched the experimental data well (r (2) of 0.75). Taken together, these results suggest that the Pi(2) resonance in resting human skeletal muscle observed at 7T provides a quantitative MR-based functional measure of mitochondrial density.