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In vivo 31P MRS detection of an alkaline inorganic phosphate pool with short T1 in human resting skeletal muscle.

ABSTRACT: Non-invasive determination of mitochondrial content is an important objective in clinical and sports medicine. 31P MRS approaches to obtain information on this parameter at low field strength typically require in-magnet exercise. Direct observation of the intra-mitochondrial inorganic phosphate (Pi) pool in resting muscle would constitute an alternative, simpler method. In this study, we exploited the higher spectral resolution and signal-to-noise at 7T to investigate the MR visibility of this metabolite pool. 31P in vivo MR spectra of the resting soleus (SOL) muscle were obtained with 1H MR image-guided surface coil localization (six volunteers) and of the SOL and tibialis anterior (TA) muscle using 2D CSI (five volunteers). A resonance at a frequency 0.38 ppm downfield from the cytosolic Pi resonance (Pi(1); pH 7.0 ± 0.04) was reproducibly detected in the SOL muscle in all subjects and conditionally attributed to the intra-mitochondrial Pi pool (Pi(2); pH 7.3 ± 0.07). In the SOL muscle, the Pi(2)/Pi(1) ratio was 1.6 times higher compared to the TA muscle in the same individual. Localized 3D CSI results showed that the Pi(2) peak was present in voxels well away from blood vessels. Determination of the T1 of the two Pi pools in a single individual using adiabatic excitation of the spectral region around 5 ppm yielded estimates of 4.3 ± 0.4 s vs 1.4 ± 0.5 s for Pi(1) and Pi(2), respectively. Together, these results suggest that the intra-mitochondrial Pi pool in resting human skeletal muscle may be visible with 31P MRS at high field.

SUBMITTER: Kan HE

PROVIDER: S-EPMC3856567 | biostudies-other | 2010 Oct

REPOSITORIES: biostudies-other

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Project description:Intramuscular hydrogen ion (H+ ) and inorganic phosphate (Pi) concentrations were dissociated during exercise to challenge their relationships with peripheral and central fatigue in vivo. Ten recreationally active, healthy men (27 ± 5 years; 180 ± 4 cm; 76 ± 10 kg) performed two consecutive intermittent isometric single-leg knee-extensor trials (60 maximal voluntary contractions; 3 s contraction, 2 s relaxation) interspersed with 5 min of rest. Phosphorus magnetic resonance spectroscopy (31 P-MRS) was used to continuously quantify intramuscular [H+ ] and [Pi] during both trials. Using electrical femoral nerve stimulation, quadriceps twitch force (Qtw ) and voluntary activation (VA) were quantified at rest and throughout both trials. Decreases in Qtw and VA from baseline were used to determine peripheral and central fatigue, respectively. Qtw was strongly related to both [H+ ] (β coefficient: -0.9, P < 0.0001) and [Pi] (-1.1, P < 0.0001) across trials. There was an effect of trial on the relationship between Qtw and [H+ ] (-0.5, P < 0.0001), but not Qtw and [Pi] (0.0, P = 0.976). This suggests that, unlike the unaltered association with [Pi], a given level of peripheral fatigue was associated with a different [H+ ] in Trial 1 vs. Trial 2. VA was related to [H+ ] (-0.3, P < 0.0001), but not [Pi] (-0.2, P = 0.243), across trials and there was no effect of trial (-0.1, P = 0.483). Taken together, these results support intramuscular Pi as a primary cause of peripheral fatigue, and muscle acidosis, probably acting on group III/IV muscle afferents in the interstitial space, as a contributor to central fatigue during exercise. KEY POINTS: We investigated the relationship between intramuscular metabolites and neuromuscular function in humans performing two maximal, intermittent, knee-extension trials interspersed with 5 min of rest. Concomitant measurements of intramuscular hydrogen (H+ ) and inorganic phosphate (Pi) concentrations, as well as quadriceps twitch-force (Qtw ) and voluntary activation (VA), were made throughout each trial using phosphorus magnetic resonance spectroscopy (31 P-MRS) and electrical femoral nerve stimulations. Although [Pi] fully recovered prior to the onset of the second trial, [H+ ] did not. Qtw was strongly related to both [H+ ] and [Pi] across both trials. However, the relationship between Qtw and [H+ ] shifted leftward from the first to the second trial, whereas the relationship between Qtw and [Pi] remained unaltered. VA was related to [H+ ], but not [Pi], across both trials. These in vivo findings support the hypotheses of intramuscular Pi as a primary cause of peripheral fatigue, and muscle acidosis, probably acting on group III/IV muscle afferents, as a contributor to central fatigue.

Project description:Phosphorus is essential in all cells' structural, metabolic and regulatory functions. For fungal cells that import inorganic phosphate (Pi) up a steep concentration gradient, surface Pi transporters are critical capacitators of growth. Fungi must deploy Pi transporters that enable optimal Pi uptake in pH and Pi concentration ranges prevalent in their environments. Single, triple and quadruple mutants were used to characterize the four Pi transporters we identified for the human fungal pathogen Candida albicans, which must adapt to alkaline conditions during invasion of the host bloodstream and deep organs. A high-affinity Pi transporter, Pho84, was most efficient across the widest pH range while another, Pho89, showed high-affinity characteristics only within one pH unit of neutral. Two low-affinity Pi transporters, Pho87 and Fgr2, were active only in acidic conditions. Only Pho84 among the Pi transporters was clearly required in previously identified Pi-related functions including Target of Rapamycin Complex 1 signaling, oxidative stress resistance and hyphal growth. We used in vitro evolution and whole genome sequencing as an unbiased forward genetic approach to probe adaptation to prolonged Pi scarcity of two quadruple mutant lineages lacking all 4 Pi transporters. Lineage-specific genomic changes corresponded to divergent success of the two lineages in fitness recovery during Pi limitation. Initial, large-scale genomic alterations like aneuploidies and loss of heterozygosity eventually resolved, as populations gained small-scale mutations. Severity of some phenotypes linked to Pi starvation, like cell wall stress hypersensitivity, decreased in parallel to evolving populations' fitness recovery in Pi scarcity, while severity of others like membrane stress responses diverged from Pi scarcity fitness. Among preliminary candidate genes for contributors to fitness recovery, those with links to TORC1 were overrepresented. Since Pi homeostasis differs substantially between fungi and humans, adaptive processes to Pi deprivation may harbor small-molecule targets that impact fungal growth, stress resistance and virulence.

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In vivo 31P MRS detection of an alkaline inorganic phosphate pool with short T1 in human resting skeletal muscle.

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