31P-Magnetization Transfer Magnetic Resonance Spectroscopy Measurements of In Vivo Metabolism

Abstract

Magnetic resonance spectroscopy offers a broad range of noninvasive analytical methods for investigating metabolism in vivo. Of these, the magnetization-transfer (MT) techniques permit the estimation of the unidirectional fluxes associated with metabolic exchange reactions. Phosphorus (31P) MT measurements can be used to examine the bioenergetic reactions of the creatine-kinase system and the ATP synthesis/hydrolysis cycle. Observations from our group and others suggest that the inorganic phosphate (Pi) → ATP flux in skeletal muscle may be modulated by certain conditions, including aging, insulin resistance, and diabetes, and may reflect inherent alterations in mitochondrial metabolism. However, such effects on the Pi → ATP flux are not universally observed under conditions in which mitochondrial function, assessed by other techniques, is impaired, and recent articles have raised concerns about the absolute magnitude of the measured reaction rates. As the application of 31P-MT techniques becomes more widespread, this article reviews the methodology and outlines our experience with its implementation in a variety of models in vivo. Also discussed are potential limitations of the technique, complementary methods for assessing oxidative metabolism, and whether the Pi → ATP flux is a viable biomarker of metabolic function in vivo.

Ectopic lipid storage in non-alcoholic fatty liver disease is not mediated by impaired mitochondrial oxidative capacity in skeletal muscle

“…Interestingly, a cross-sectional study of 15 normal subjects [36], significant correlations were found between the resting Pi-ATP exchange rate and a restingischaemia 31 P MRS measure of resting ATP synthesis rate (despite the order-of-magnitude difference in absolute numbers), and PCr-recovery based measures of mitochondrial function (despite the logical distinctness of ATP turnover and oxidative capacity, as mentioned above, and for reasons which are so far unexplained [10]. This first of these correlations, together with some observations of clinical or experimental changes in Pi-ATP exchange in physiologically expected directions [37] (again, notwithstanding the order-of-magnitude error), is sometimes described as supporting [37] or even validating [30] the Pi-ATP exchange measurement. However, as almost nothing is known about what determines the overwhelmingly dominant non-mitochondrial component of the measurement [10], this interpretation remains problematic.…”

Assessing tissue metabolism by phosphorous-31 magnetic resonance spectroscopy and imaging: a methodology review

“…Since then, this technique has been widely applied to measure CK reaction rate in heart, brain, and skeletal muscle (17,73,(112)(113)(114)(115)(116)(117). P i -to-ATP flux has also been investigated in liver, heart, Quant Imaging Med Surg 2017;7(6):707-726 qims.amegroups.com brain, and skeletal muscle (17,(118)(119)(120)(121). Metabolic abnormalities associated with various diseases including diabetes (17,120), heart failure (7), and stroke (122) have also been evaluated using this technique.…”

“…Since each acquisition is followed by a long waiting period to reestablish the equilibrium conditions, acquisition time of an MT experiment is typically very long, with waiting time amounts to >90% of the total acquisition time. Further, due to the relatively small signal change in P i (~20%), quantification of ATP synthesis rate via ATP synthase has been quite limited (17).…”

“…However, the use of long saturation pulses may not always be practical on clinical scanners. Further, the underlying mechanisms of some ST effects are still being debated (12,17,125,126). Several studies have used inversion transfer (IT) to quantify exchange kinetics (127-129).…”

Lower Fasting Muscle Mitochondrial Activity Relates to Hepatic Steatosis in Humans

“…The applied saturation transfer method for assessing fATP by means of 31 P-MRS has been validated in a variety of in vitro systems and in human muscle biopsy samples, as reviewed recently (37). The limitations of this approach are that this method provides a measure of ATP synthesis/ hydrolysis cycle at rest driven by energy demands rather than maximal oxidative capacity and that differences in individual mitochondrial content are not taken into account.…”