The purpose of this study was to evaluate temporal stability, multi‐center reproducibility and the influence of covariates on a multimodal MR protocol for quantitative muscle imaging and to ...facilitate its use as a standardized protocol for evaluation of pathology in skeletal muscle.
Quantitative T2, quantitative diffusion and four‐point Dixon acquisitions of the calf muscles of both legs were repeated within one hour. Sixty‐five healthy volunteers (31 females) were included in one of eight 3‐T MR systems. Five traveling subjects were examined in six MR scanners. Average values over all slices of water‐T2 relaxation time, proton density fat fraction (PDFF) and diffusion metrics were determined for seven muscles. Temporal stability was tested with repeated measured ANOVA and two‐way random intraclass correlation coefficient (ICC). Multi‐center reproducibility of traveling volunteers was assessed by a two‐way mixed ICC. The factors age, body mass index, gender and muscle were tested for covariance.
ICCs of temporal stability were between 0.963 and 0.999 for all parameters. Water‐T2 relaxation decreased significantly (P < 10−3) within one hour by ~ 1 ms. Multi‐center reproducibility showed ICCs within 0.879–0.917 with the lowest ICC for mean diffusivity. Different muscles showed the highest covariance, explaining 20–40% of variance for observed parameters.
Standardized acquisition and processing of quantitative muscle MRI data resulted in high comparability among centers. The imaging protocol exhibited high temporal stability over one hour except for water T2 relaxation times. These results show that data pooling is feasible and enables assembling data from patients with neuromuscular diseases, paving the way towards larger studies of rare muscle disorders.
Quantitative MR images from calf muscles were evaluated from eight different scanners and a traveling cohort. Standardized acquisition protocols and processing methods allow for highly reproducible quantitative (water‐T2, Dixon proton density fat fraction and DTI parameters) descriptions of muscle status. The temporal order of scans plays a key role when assessing T2 relaxation times. Data from different centers (but the same vendor with identical acquisition and processing) could be pooled in one database when the same scanning protocol is used.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Acute kidney injury (AKI) causes severe morbidity, mortality, and chronic kidney disease (CKD). Mortality is particularly marked in the elderly and with preexisting CKD. Oxidative stress is a common ...theme in models of AKI induced by ischemia-reperfusion (I-R) injury. We recently characterized an intracellular isoform of matrix metalloproteinase-2 (MMP-2) induced by oxidative stress-mediated activation of an alternate promoter in the first intron of the MMP-2 gene. This generates an NH
-terminal truncated MMP-2 (NTT-MMP-2) isoform that is intracellular and associated with mitochondria. The NTT-MMP-2 isoform is expressed in kidneys of 14-mo-old mice and in a mouse model of coronary atherosclerosis and heart failure with CKD. We recently determined that NTT-MMP-2 is induced in human renal transplants with delayed graft function and correlated with tubular cell necrosis. To determine mechanism(s) of action, we generated proximal tubule cell-specific NTT-MMP-2 transgenic mice. Although morphologically normal at the light microscopic level at 4 mo, ultrastructural studies revealed foci of tubular epithelial cell necrosis, the mitochondrial permeability transition, and mitophagy. To determine whether NTT-MMP-2 expression enhances sensitivity to I-R injury, we performed unilateral I-R to induce mild tubular injury in wild-type mice. In contrast, expression of the NTT-MMP-2 isoform resulted in a dramatic increase in tubular cell necrosis, inflammation, and fibrosis. NTT-MMP-2 mice had enhanced expression of innate immunity genes and release of danger-associated molecular pattern molecules. We conclude that NTT-MMP-2 "primes" the kidney to enhanced susceptibility to I-R injury via induction of mitochondrial dysfunction. NTT-MMP-2 may be a novel AKI treatment target.
Contusion spinal cord injury (SCI) animal models are used to study loss of muscle function and mass. However, parallels to the human condition typically have been confounded by spontaneous recovery ...observed within the first few post-injury weeks, partly because of free cage activity. We implemented a new rat model combining SCI with cast immobilization (IMM) to more closely reproduce the unloading conditions experienced by SCI patients. Magnetic resonance imaging was used to monitor hindlimb muscles' cross-sectional area (CSA) after SCI, IMM alone, SCI combined with IMM (SCI+IMM), and in controls (CTR) over a period of 21 days. Soleus muscle tetanic force was measured in situ on day 21, and hindlimb muscles were harvested for histology. IMM alone produced a decrease in triceps surae CSA to 63.9±4.9% of baseline values within 14 days. In SCI, CSA decreased to 75.0±10.5% after 7 days, and recovered to 77.9±10.7% by day 21. SCI+IMM showed the greatest amount of atrophy (56.9±9.9% on day 21). In all groups, muscle mass and soleus tetanic force decreased in parallel, such that specific force was maintained. Extensor digitorum longus (EDL) and soleus fiber size decreased in all groups, particularly in SCI+IMM. We observed a significant degree of asymmetry in muscle CSA in SCI but not IMM. This effect increased between day 7 and 21 in SCI, but also in SCI+IMM, suggesting a minor dependence on muscle activity. SCI+IMM offers a clinically relevant model of SCI to investigate the mechanistic basis for skeletal muscle adaptations after SCI and develop therapeutic approaches.
Purpose
Muscle paralysis after spinal cord injury leads to muscle atrophy, enhanced muscle fatigue, and increased energy demands for functional activities. Phosphorus magnetic resonance spectroscopy ...(
31
P-MRS) offers a unique non-invasive alternative of measuring energy metabolism in skeletal muscle and is especially suitable for longitudinal investigations. We determined the impact of spinal cord contusion on in vivo muscle bioenergetics of the rat hind limb muscle using
31
P-MRS.
Methods
A moderate spinal cord contusion injury (cSCI) was induced at the T8–T10 thoracic spinal segments.
31
P-MRS measurements were performed weekly in the rat hind limb muscles for 3 weeks. Spectra were acquired in a Bruker 11 T/470 MHz spectrometer using a 31P surface coil. The sciatic nerve was electrically stimulated by subcutaneous needle electrodes. Spectra were acquired at rest (5 min), during stimulation (6 min), and recovery (20 min). Phosphocreatine (PCr) depletion rates and the pseudo first-order rate constant for PCr recovery (
k
PCr
) were determined. The maximal rate of PCr resynthesis, the in vivo maximum oxidative capacity (
V
max
) and oxidative adenosine triphosphate (ATP) synthesis rate (
Q
max
) were subsequently calculated.
Results
One week after cSCI, there was a decline in the resting total creatine of the paralyzed muscle. There was a significant reduction (~24 %) in
k
PCr
measures of the paralyzed muscle, maximum in vivo mitochondrial capacity (
V
max
) and the maximum oxidative ATP synthesis rate (
Q
max
) at 1 week post-cSCI. During exercise, the PCr depletion rates in the paralyzed muscle one week after injury were rapid and to a greater extent than in a healthy muscle.
Conclusions
Using in vivo MRS assessments, we reveal an acute oxidative metabolic defect in the paralyzed hind limb muscle. These altered muscle bioenergetics might contribute to the host of motor dysfunctions seen after cSCI.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The cerebral metabolic rate of oxygen consumption (CMRO2) is a key metric to investigate the mechanisms involved in neurodegeneration in animal models and evaluate potential new therapies. CMRO2 can ...be measured by direct 17O magnetic resonance imaging (17O-MRI) of H217O signal changes during inhalation of 17O-labeled oxygen gas. In this study, we built a simple gas distribution system and used 3D zero echo time (ZTE-)MRI at 11.7 T to measure CMRO2 in the APPswe/PS1dE9 mouse model of amyloidosis. We found that CMRO2 was significantly lower in the APPswe/PS1dE9 brain than in wild-type at 12–14 months. We also estimated cerebral blood flow (CBF) from the post-inhalation washout curve and found no difference between groups. These results suggest that the lower CMRO2 observed in APPswe/PS1dE9 is likely due to metabolism impairment rather than to reduced blood flow. Analysis of the 17O-MRI data using different quantification models (linear and 3-phase model) showed that the choice of the model does not affect group comparison results. However, the simplified linear model significantly underestimated the absolute CMRO2 values compared to a 3-phase model. This may become of importance when combining several metabolic fluxes measurements to study neuro-metabolic coupling.
Acute kidney injury (AKI) is a major risk factor for the development of chronic kidney disease (CKD). Persistent oxidative stress and mitochondrial dysfunction are implicated across diverse forms of ...AKI and in the transition to CKD. In this study, we applied hyperpolarized (HP) 13C dehydroascorbate (DHA) and 13C pyruvate magnetic resonance spectroscopy (MRS) to investigate the renal redox capacity and mitochondrial pyruvate dehydrogenase (PDH) activity, respectively, in a murine model of AKI at baseline and 7 days after unilateral ischemia reperfusion injury (IRI). Compared with the contralateral sham‐operated kidneys, the kidneys subjected to IRI showed a significant decrease in the HP 13C vitamin C/(vitamin C + DHA) ratio, consistent with a decrease in redox capacity. The kidneys subjected to IRI also showed a significant decrease in the HP 13C bicarbonate/pyruvate ratio, consistent with impaired PDH activity. The IRI kidneys showed a significantly higher HP 13C lactate/pyruvate ratio at day 7 compared with baseline, although the 13C lactate/pyruvate ratio was not significantly different between the IRI and contralateral sham‐operated kidneys at day 7. Arterial spin labeling magnetic resonance imaging (MRI) demonstrated significantly reduced perfusion in the IRI kidneys. Renal tissue analysis showed corresponding increased reactive oxygen species (ROS) and reduced PDH activity in the IRI kidneys. Our results show the feasibility of HP 13C MRS for the non‐invasive assessment of oxidative stress and mitochondrial PDH activity following renal IRI.
We have shown that hyperpolarized 13C dehydroascorbate and 13C pyruvate magnetic resonance spectroscopy can be used to non‐invasively assess the altered renal redox capacity and mitochondrial pyruvate dehydrogenase (PDH) activity following ischemia reperfusion injury in a murine model. Such an imaging approach can potentially enhance the prediction and monitoring of progressive kidney injury.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Optimal treatment selection for localized renal tumors is challenging due to their variable biological behavior and limited ability to pre-operatively assess their aggressiveness. We investigated ...hyperpolarized (HP) 13C pyruvate MRI to noninvasively assess tumor lactate production and compartmentalization, which are strongly associated with renal tumor aggressiveness. Orthotopic tumors were created in mice using human renal cell carcinoma (RCC) lines (A498, 786-O, UOK262) with varying expression of lactate dehydrogenase A (LDHA) which catalyzes the pyruvate-to-lactate conversion, and varying expression of monocarboxylate transporter 4 (MCT4) which mediates lactate export out of the cells. Dynamic HP 13C pyruvate MRI showed that the A498 tumors had significantly higher 13C pyruvate-to-lactate conversion than the UOK262 and 786-O tumors, corresponding to higher A498 tumor LDHA expression. Additionally, diffusion-weighted HP 13C pyruvate MRI showed that the A498 tumors had significantly higher 13C lactate apparent diffusion coefficients compared to 786-O tumors, with corresponding higher MCT4 expression, which likely reflects more rapid lactate export in the A498 tumors. Our data demonstrate the feasibility of HP 13C pyruvate MRI to inform on tumor lactate production and compartmentalization, and provide the scientific premise for future clinical investigation into the utility of this technique to noninvasively interrogate renal tumor aggressiveness and to guide treatment selection.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The development of therapeutic clinical trials for glycogen storage disorders, including Pompe disease, has called for non-invasive and objective biomarkers. Glycogen accumulation can be measured ...in vivo with
13
C MRS. However, clinical implementation remains challenging due to low signal-to-noise. On the other hand, the buildup of glycolytic intermediates may be detected with
31
P MRS. We sought to identify new biomarkers of disease progression in muscle using
13
C/
31
P MRS and
1
H HR-MAS in a mouse model of Pompe disease (
Gaa
−/−
). We evaluated the sensitivity of these MR biomarkers in vivo after treatment using an adeno-associated virus vector 2/9 encoding hGAA driven by the desmin promotor.
31
P MRS showed significantly elevated phosphomonoesters (PMEs) in
Gaa
−/−
compared to control at 2 (0.06 ± 0.02 versus 0.03 ± 0.01; p = 0.003), 6, 12, and 18 months of age. Correlative
1
H HR-MAS measures in intact gastrocnemius muscles revealed high glucose-6-phosphate (G-6-P). After intramuscular AAV injections, glycogen, PME, and G-6-P were decreased within normal range. The changes in PME levels likely partly resulted from changes in G-6-P, one of the overlapping phosphomonoesters in the
31
P MR spectra in vivo. Because
31
P MRS is inherently more sensitive than
13
C MRS, PME levels have greater potential as a clinical biomarker and should be considered as a complementary approach for future studies in Pompe patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
Skeletal muscle phosphorus‐31 31P MRS is the oldest MRS methodology to be applied to in vivo metabolic research. The technical requirements of 31P MRS in skeletal muscle depend on the research ...question, and to assess those questions requires understanding both the relevant muscle physiology, and how 31P MRS methods can probe it. Here we consider basic signal‐acquisition parameters related to radio frequency excitation, TR, TE, spectral resolution, shim and localisation. We make specific recommendations for studies of resting and exercising muscle, including magnetisation transfer, and for data processing. We summarise the metabolic information that can be quantitatively assessed with 31P MRS, either measured directly or derived by calculations that depend on particular metabolic models, and we give advice on potential problems of interpretation. We give expected values and tolerable ranges for some measured quantities, and minimum requirements for reporting acquisition parameters and experimental results in publications. Reliable examination depends on a reproducible setup, standardised preconditioning of the subject, and careful control of potential difficulties, and we summarise some important considerations and potential confounders. Our recommendations include the quantification and standardisation of contraction intensity, and how best to account for heterogeneous muscle recruitment. We highlight some pitfalls in the assessment of mitochondrial function by analysis of phosphocreatine (PCr) recovery kinetics. Finally, we outline how complementary techniques (near‐infrared spectroscopy, arterial spin labelling, BOLD and various other MRI and 1H MRS measurements) can help in the physiological/metabolic interpretation of 31P MRS studies by providing information about blood flow and oxygen delivery/utilisation. Our recommendations will assist in achieving the fullest possible reliable picture of muscle physiology and pathophysiology.
31P MRS can usefully probe skeletal muscle cellular energy metabolism. Choice of methodology depends on the research question. The recommendations given here will help researchers experienced in general MRS with the application of 31P MRS in skeletal muscle, covering the practicalities of data acquisition and muscle exercise as well as the physiological interpretation of the measurements. We also give expected values and tolerable ranges for some measured quantities, and minimum requirements for reporting results and acquisition parameters.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Early diagnosis and follow-up of neurodegenerative diseases are often hampered by the lack of reliable biomarkers. Neuroimaging techniques like magnetic resonance spectroscopy (MRS) offer promising ...tools to detect biochemical alterations at early stages of degeneration. Intracellular pH, which can be measured noninvasively by 31P-MRS, has shown variations in several brain diseases. Our purpose has been to evaluate the potential of MRS-measured pH as a relevant biomarker of early degeneration in Huntington's disease (HD). We used a translational approach starting with a preclinical validation of our hypothesis before adapting the method to HD patients. 31P-MRS-derived cerebral pH was first measured in rodents during chronic intoxication with 3-nitropropionic acid (3NP). A significant pH increase was observed early into the intoxication protocol (pH = 7.17 ± 0.02 after 3 days) as compared with preintoxication (pH = 7.08 ± 0.03). Furthermore, pH changes correlated with the 3NP-induced inhibition of succinate dehydrogenase and preceded striatum lesions. Using a similar MRS approach implemented on a clinical MRI, we then showed that cerebral pH was significantly higher in HD patients (n = 7) than in healthy controls (n = 6) (7.05 ± 0.03 versus 7.02 ± 0.01, respectively, P = 0.026). Altogether, both preclinical and human data strongly argue in favor of MRS-measured pH being a promising biomarker for diagnosis and follow-up of HD.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
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