Going to ultrahigh field MRI (e.g., 7 Tesla [T]), the nonuniformity of the B1+ field and the increased radiofrequency (RF) power deposition become challenging. While surface coils improve the power efficiency in B1+, its field remains nonuniform. In this work, an RF pulse was designed that uses the slab selection to compensate the inhomogeneous B1+ field of a surface coil without a substantial increase in specific absorption rate (SAR).
Over the last decade, the field of cancer metabolism has mainly focused on studying the role of tumorigenic metabolic rewiring in supporting cancer proliferation. Here, we perform the first genome-scale computational study of the metabolic underpinnings of cancer migration. We build genome-scale metabolic models of the NCI-60 cell lines that capture the Warburg effect (aerobic glycolysis) typically occurring in cancer cells. The extent of the Warburg effect in each of these cell line models is quantified by the ratio of glycolytic to oxidative ATP flux (AFR), which is found to be highly positively associated with cancer cell migration. We hence predicted that targeting genes that mitigate the Warburg effect by reducing the AFR may specifically inhibit cancer migration. By testing the anti-migratory effects of silencing such 17 top predicted genes in four breast and lung cancer cell lines, we find that up to 13 of these novel predictions significantly attenuate cell migration either in all or one cell line only, while having almost no effect on cell proliferation. Furthermore, in accordance with the predictions, a significant reduction is observed in the ratio between experimentally measured ECAR and OCR levels following these perturbations. Inhibiting anti-migratory targets is a promising future avenue in treating cancer since it may decrease cytotoxic-related side effects that plague current anti-proliferative treatments. Furthermore, it may reduce cytotoxic-related clonal selection of more aggressive cancer cells and the likelihood of emerging resistance.
The pyruvate dehydrogenase complex (PDC) catalyzes the conversion of pyruvate into acetyl-CoA, a critical step in metabolism. Sutendra et al. now demonstrate that PDC can translocate from the mitochondria to the nucleus to provide acetyl-CoA necessary for histone acetylation, suggesting a new pathway for mitochondrial-nuclear communication.
Lipid suppression in MR brain imaging and spectroscopy has been a long-standing problem for which various techniques have been developed. Most methods are based on inversion recovery or spatially or spectrally selective excitation of the lipid signal followed by dephasing. All techniques require additional RF pulses, gradient crushers and delays, which increase the duration and complexity of sequences. In addition, the lipid signal is poorly shimmed, and is composed of different resonance frequencies that have different relaxation properties.
Mitochondria integrate metabolic networks for maintaining bioenergetic requirements. Deregulation of mitochondrial metabolic networks can lead to mitochondrial dysfunction, which is a common hallmark of many diseases. Reversible post-translational protein acetylation modifications are emerging as critical regulators of mitochondrial function and form a direct link between metabolism and protein function, via the metabolic intermediate acetyl-CoA. Sirtuins catalyze protein deacetylation, but how mitochondrial acetylation is determined is unclear. We report here a mechanism that explains mitochondrial protein acetylation dynamics in vivo. Food withdrawal in mice induces a rapid increase in hepatic protein acetylation. Furthermore, using a novel LC-MS/MS method, we were able to quantify protein acetylation in human fibroblasts. We demonstrate that inducing fatty acid oxidation in fibroblasts increases protein acetylation. Furthermore, we show by using radioactively labeled palmitate that fatty acids are a direct source for mitochondrial protein acetylation. Intriguingly, in a mouse model that resembles human very-long chain acyl-CoA dehydrogenase (VLCAD) deficiency, we demonstrate that upon food-withdrawal, hepatic protein hyperacetylation is absent. This indicates that functional fatty acid oxidation is necessary for protein acetylation to occur in the liver upon food withdrawal. Furthermore, we now demonstrate that protein acetylation is abundant in human liver peroxisomes, an organelle where acetyl-CoA is solely generated by fatty acid oxidation. Our findings provide a mechanism for metabolic control of protein acetylation, which provides insight into the pathophysiogical role of protein acetylation dynamics in fatty acid oxidation disorders and other metabolic diseases associated with mitochondrial dysfunction.
Inherited disorders of acyl-CoA metabolism, such as defects in amino acid metabolism and fatty acid oxidation can present with severe clinical symptoms either neonatally or later in life, but the pathophysiological mechanisms are often incompletely understood. We now report the discovery of a novel biochemical mechanism that could contribute to the pathophysiology of these disorders. We identified increased protein lysine butyrylation in short-chain acyl-CoA dehydrogenase (SCAD) deficient mice as a result of the accumulation of butyryl-CoA. Similarly, in SCAD deficient fibroblasts, lysine butyrylation was increased. Furthermore, malonyl-CoA decarboxylase (MCD) deficient patient cells had increased levels of malonylated lysines and propionyl-CoA carboxylase (PCC) deficient patient cells had increased propionylation of lysines. Since lysine acylation can greatly impact protein function, aberrant lysine acylation in inherited disorders associated with acyl-CoA accumulation may well play a role in their disease pathophysiology.
The increased magnetic susceptibility effects at higher magnetic fields increase the demands for shimming of the B0 field for in vivo MRI and MRS. Both static and dynamic techniques have been developed to compensate for susceptibility-induced field inhomogeneities. In this study, we investigate the impact of and need for both static and dynamic higher order B0 shimming of magnetic field homogeneities in clinical breast MRI at 7 T. Both global and local field variations at lipid-tissue interfaces were observed in the magnetic field using TE-optimized B0 mapping at 7 T. With static B0 shimming, a field homogeneity of 39 ± 11 Hz (n = 48) was reached in a single breast using second-order shimming. Further compensation of the residual local field inhomogeneities caused by lipid-tissue interfaces does not seem to be feasible with shallow spherical harmonic fields. For bilateral shimming, the shimming quality was significantly less at 62 ± 15 Hz (n = 22) over both breasts, even after (simulated) fourth-order shimming. In addition, a substantial time-dependent field instability of 30 Hz peak to peak, with significant higher order field contributions, was observed during regular breathing. In conclusion, TE-optimized B0 field mapping reveals substantial field variations in the lipid-rich environment of the human breast, in both space and time. The static field variations could be partially minimized by third-order B0 shimming, providing sufficient lipid suppression. However, in order to fully benefit from the increased spectral dispersion at high fields, the significant magnetic field variations during breathing need to be considered.
Schizophrenia is characterized by loss of brain volume, which may represent an ongoing pathophysiological process. This loss of brain volume may be explained by reduced neuropil rather than neuronal loss, suggesting abnormal synaptic plasticity and cortical microcircuitry. A possible mechanism is hypofunction of the NMDA-type of glutamate receptor, which reduces the excitation of inhibitory GABAergic interneurons, resulting in a disinhibition of glutamatergic pyramidal neurons. Disinhibition of pyramidal cells may result in excessive stimulation by glutamate, which in turn could cause neuronal damage or death through excitotoxicity. In this study, GABA/creatine ratios, and glutamate, NAA, creatine and choline concentrations in the prefrontal and parieto-occipital cortices were measured in 17 patients with schizophrenia and 23 healthy controls using proton magnetic resonance spectroscopy at an ultra-high magnetic field strength of 7 T. Significantly lower GABA/Cr ratios were found in patients with schizophrenia in the prefrontal cortex as compared to healthy controls, with GABA/Cr ratios inversely correlated with cognitive functioning in the patients. No significant change in the GABA/Cr ratio was found between patients and controls in the parieto-occipital cortex, nor were levels of glutamate, NAA, creatine, and choline differed in patients and controls in the prefrontal and parieto-occipital cortices. Our findings support a mechanism involving altered GABA levels distinguished from glutamate levels in the medial prefrontal cortex in schizophrenia, particularly in high functioning patients. A (compensatory) role for GABA through altered inhibitory neurotransmission in the prefrontal cortex may be ongoing in (higher functioning) patients with schizophrenia.
Sirtuins are a family of protein deacetylases, deacylases, and ADP-ribosyltransferases that regulate life span, control the onset of numerous age-associated diseases, and mediate metabolic homeostasis. We have uncovered a novel role for the mitochondrial sirtuin SIRT4 in the regulation of hepatic lipid metabolism during changes in nutrient availability. We show that SIRT4 levels decrease in the liver during fasting and that SIRT4 null mice display increased expression of hepatic peroxisome proliferator-activated receptor ? (PPAR?) target genes associated with fatty acid catabolism. Accordingly, primary hepatocytes from SIRT4 knockout (KO) mice exhibit higher rates of fatty acid oxidation than wild-type hepatocytes, and SIRT4 overexpression decreases fatty acid oxidation rates. The enhanced fatty acid oxidation observed in SIRT4 KO hepatocytes requires functional SIRT1, demonstrating a clear cross talk between mitochondrial and nuclear sirtuins. Thus, SIRT4 is a new component of mitochondrial signaling in the liver and functions as an important regulator of lipid metabolism.
Lipid metabolism is tightly controlled by the nutritional state of the organism. Nutrient-rich conditions increase lipogenesis, whereas nutrient deprivation promotes fat oxidation. In this study, we identify the mitochondrial sirtuin, SIRT4, as a regulator of lipid homeostasis. SIRT4 is active in nutrient-replete conditions to repress fatty acid oxidation while promoting lipid anabolism. SIRT4 deacetylates and inhibits malonyl CoA decarboxylase (MCD), an enzyme that produces acetyl CoA from malonyl CoA. Malonyl CoA provides the carbon skeleton for lipogenesis and also inhibits fat oxidation. Mice lacking SIRT4 display elevated MCD activity and decreased malonyl CoA in skeletal muscle and white adipose tissue. Consequently, SIRT4 KO mice display deregulated lipid metabolism, leading to increased exercise tolerance and protection against diet-induced obesity. In sum, this work elucidates SIRT4 as an important regulator of lipid homeostasis, identifies MCD as a SIRT4 target, and deepens our understanding of the malonyl CoA regulatory axis.
Large dynamic fluctuations of the static magnetic field (B(0)) are observed in the human body during MR scanning, compromising image quality and detection sensitivity in several MR imaging and spectroscopy sequences. Partially, these dynamic B(0) fluctuations are due to physiological motion such as breathing, but other sources of temporal B(0) field fluctuations are also present in the MR system (e.g., eddy currents). Especially at ultrahigh field (?7 T), the increased susceptibility effects lead to large B(0) field variations over time. Direct measurement and correction of these temporal field variations of up to 70 Hz will lead to a significant reduction of artifacts and improved measurement stability/reproducibility. For direct measurement of the temporally changing B(0) field, a simple field probe was developed, that was placed in proximity to the tissue of interest. In this work, it is shown how such a field probe system can be used to monitor temporal B(0) field variations in the human body during MRI and magnetic resonance spectroscopy. Furthermore, it is shown how the acquired temporal B(0) field information can drive a dynamic shim module to directly correct the B(0) magnetic field in real time.
At high field (7 T) spectral editing of ?-aminobutyric acid with MEGA-point-resolved spectroscopy is inefficient due to the large chemical shift displacement error. In this article, a new pulse sequence is designed which has minimal chemical shift displacement error to perform an efficient spectral editing of the ?-aminobutyric acid 3.0 ppm resonance at 7 T. The sequence consists of the conventional MEGA editing pulses and a semi-localized by adiabatic selective refocusing sequence. Phantom and in vivo measurements demonstrated an efficient detection of ?-aminobutyric acid. Using ECG triggering, excellent in vivo performance of the MEGA-semi-localized by adiabatic selective refocusing (MEGA-sLASER) provided well-resolved ?-aminobutyric acid signals in 27 mL volumes in the human brain at an echo time of 74 ms within a relatively short acquisition time (5 min). Furthermore, the high efficiency of the MEGA-sLASER was demonstrated by acquiring small volumes (8 mL) at an echo time of 74 ms, as well as long echo time measurements (222 ms in 27 mL volume).
Nonuniform B(1) fields in ultrahigh-field MR imaging cause severe image artifacts, when conventional radiofrequency (RF) pulses are used. Particularly in MR sequences that encompass multiple RF pulses, e.g., turbo spin echo (TSE) sequences, complete signal loss may occur in certain areas. When using a surface coil for transmitting the RF pulses, these problems become even more challenging, as the spatial B(1) field variance is substantial. As an alternative to conventional TSE sequences, adiabatic TSE sequences can be applied, which have the benefit that these sequences are insensitive to B(1) nonuniformity. In this study, we investigate the potential of using adiabatic TSE at 7 T with surface coil transceivers in human applications. The adiabatic RF pulses were tuned to deal with the constraints in B(1) strength and RF power deposition, but remained in the superadiabatic regime. As a consequence, the dynamic range in B(1) is compromised, and signal modulation is obtained over the echo train. Multidimensional Bloch simulations over the echo train and phantom measurements were obtained to assess these limitations. Still, using proper k-space sampling, we demonstrate improved image quality of the adiabatic TSE versus conventional TSE in the brain, the neck (carotid artery) and in the pelvis (prostate) at 7 T.
Proton MR spectroscopic imaging of the human brain at ultra-high field (?7 T) is challenging due to increased radio frequency power deposition, increased magnetic field B(0) inhomogeneity, and increased radio frequency magnetic field inhomogeneity. In addition, especially for multislice sequences, these effects directly inhibit the potential gains of higher magnetic field and can even cause a reduction in data quality. However, recent developments in dynamic B(0) magnetic field shimming and dynamic multitransmit radio frequency control allow for new acquisition strategies. Therefore, in this work, slice-by-slice B(0) and B(1) shimming was developed to optimize both B(0) magnetic field homogeneity and nutation angle over a large portion of the brain. Together with a low-power water and lipid suppression sequence and pulse-acquire spectroscopic imaging, a multislice MR spectroscopic imaging sequence is shown to be feasible at 7 T. This now allows for multislice metabolic imaging of the human brain with high sensitivity and high chemical shift resolution at ultra-high field.
High quality magnetic field homogenization of the human brain (i.e. shimming) for MR imaging and spectroscopy is a demanding task. The susceptibility differences between air and tissue are a longstanding problem as they induce complex field distortions in the prefrontal cortex and the temporal lobes. To date, the theoretical gains of high field MR have only been realized partially in the human brain due to limited magnetic field homogeneity. A novel shimming technique for the human brain is presented that is based on the combination of non-orthogonal basis fields from 48 individual, circular coils. Custom-built amplifier electronics enabled the dynamic application of the multi-coil shim fields in a slice-specific fashion. Dynamic multi-coil (DMC) shimming is shown to eliminate most of the magnetic field inhomogeneity apparent in the human brain at 7 T and provided improved performance compared to state-of-the-art dynamic shim updating with zero through third order spherical harmonic functions. The novel technique paves the way for high field MR applications of the human brain for which excellent magnetic field homogeneity is a prerequisite.
In vivo MRS of the human brain at 7 tesla allows identification of a large number of metabolites at higher spatial resolutions than currently possible at lower field strengths. However, several challenges complicate in vivo localization and artifact suppression in MRS at high spatial resolution within a clinically feasible scan time at 7 tesla. Published MRS sequences at 7 tesla suffer from long echo times, inherent signal-to-noise ratio (SNR) loss, large chemical shift displacement artifacts or long repetition times because of excessive radiofrequency (RF) power deposition. In the present study a pulse-acquire sequence was used that does not suffer from these high field drawbacks. A slice selective excitation combined with high resolution chemical shift imaging for in-plane localization was used to limit chemical shift displacement artifacts. The pulse-acquire approach resulted in a very short echo time of 1.4?ms. A cost function guided shimming algorithm was developed to constrain frequency offsets in the excited slice, therefore adiabatic frequency selective suppression could be employed to minimize artifacts from high intensity lipids and water signals in the excited slice. The high sensitivity at a TR of 1?s was demonstrated both on a supraventricular slice as well as in an area very close to the skull in the frontal cortex at a nominal spatial resolution of 0.25 cc within a feasible scan time.
This study demonstrates the feasibility of the noninvasive determination of important biomarkers of human (breast) tumor metabolism using high-field (7-T) MRI and MRS. (31) P MRSI at this field strength was used to provide a direct method for the in vivo detection and quantification of endogenous biomarkers. These encompass phospholipid metabolism, phosphate energy metabolism and intracellular pH. A double-tuned, dual-element transceiver was designed with focused radiofrequency fields for unilateral breast imaging and spectroscopy tuned for optimized sensitivity at 7 T. T(1) -weighted three-dimensional MRI and (1) H MRS were applied for the localization and quantification of total choline compounds. (31) P MRSI was obtained within 20 min per subject and mapped in three dimensions over the breast with pixel volumes of 10 mL. The feasibility of monitoring in vivo metabolism was demonstrated in two patients with breast cancer during neoadjuvant chemotherapy, validated by ex vivo high-resolution magic angle spinning NMR and compared with data from an age-matched healthy volunteer. Concentrations of total choline down to 0.4?mM could be detected in the human breast in vivo. Levels of adenosine and other nucleoside triphosphates, inorganic phosphate, phosphocholine, phosphoethanolamine and their glycerol diesters detected in glandular tissue, as well as in tumor, were mapped over the entire breast. Altered levels of these compounds were observed in patients compared with an age-matched healthy volunteer; modulation of these levels occurred in breast tumors during neoadjuvant chemotherapy. To our knowledge, this is the first comprehensive MRI and MRS study in patients with breast cancer, which reveals detailed information on the morphology and phospholipid metabolism from volumes as small as 10 mL. This endogenous metabolic information may provide a new method for the noninvasive assessment of prognostic and predictive biomarkers in breast cancer treatment.
Oxidative stress and low antioxidant levels are implicated in the aetiology of sarcoidosis, an inflammatory disease. Quercetin is a potent dietary antioxidant that also displays anti-inflammatory activities. Consequently, the aim is to examine the effect of quercetin supplementation on markers of oxidative stress and inflammation in sarcoidosis.
The cingulum bundle is a white matter fiber bundle in the human brain that is believed to be implicated in various neurological and psychiatric diseases. Subtle disease-related differences in metabolite concentrations in the cingulum tracts that may underlie these diseases may be detected using MR spectroscopic information. However, to date, limited signal to noise and lack of spatial resolution have prevented a reliable and reproducible measurement of metabolites in the cingulum bundle in vivo. Here we propose a new method that combines MR spectroscopic imaging at 7 T with fiber tracking to select only those MR spectroscopy voxels that are actually part of the cingulum bundles. The spectra of the selected spectroscopy voxels are processed per voxel and then combined yielding one spectrum at high spectral resolution for each cingulum bundle. In this way sensitivity is increased, as large parts of the cingulum are included while partial volume effects with both gray matter and white matter from other tracts is kept to a minimum. Three healthy volunteers were scanned to assess the feasibility of the method. For all three healthy volunteers spectra for the left and right cingulum tracts were computed, partial volume fractions calculated and metabolite fractions were quantified yielding similar results suggesting that tract-based MR spectroscopy allows us to study metabolic concentrations of individual white matter fiber bundles with high sensitivity and high specificity.
An endorectal coil and an eight-element microstrip array were compared for prostate imaging at 7 T. An extensive radiofrequency safety assessment was performed with the use of finite difference time domain simulations to determine safe scan parameters. These simulations showed that the endorectal coil can deliver substantially more B(1)(+) to the prostate than can the microstrip array within the specific absorption rate safety guidelines. However, the B(1)(+) field of the endorectal coil is very inhomogeneous, which makes the use of adiabatic pulses compulsory for T(1) - or T(2) -weighted imaging. As a consequence, a full prostate examination is only possible in a feasible amount of time when the microstrip array is used for T(1) - and T(2) -weighted imaging, whereas the endorectal coil is required for spectroscopic imaging. The pulse parameters were optimised within the specific absorption rate guidelines and thereafter used to provide a good illustration of the possibilities of prostate imaging at 7 T.
Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system and has been associated with several cognitive functions that are known to change with age. In rodents and humans age-related glutamate changes have been found in several brain areas. In this cross-sectional study the presence and extent of age-associated glutamate changes in the medial frontal cortex of healthy young adults were measured. Proton magnetic resonance spectroscopy ((1)H-MRS) and brain imaging were performed at 7 T in a 2 × 2 × 2 cm(3) voxel in 33 participants between 18 and 31 years old. Glutamate concentrations and grey and white matter volume could be successfully determined at an ultra-high magnetic field strength. Glutamate concentrations were lower in older individuals (0.33 mM/year). This decline is in line with grey matter thinning in the medial frontal cortex, but could not be explained by cortical thinning alone. Therefore, the decrease in glutamate in young adulthood may be due to physiological changes rather than anatomical changes.
Cancer cells exhibit an aberrant metabolism that facilitates more efficient production of biomass and hence tumor growth and progression. However, the genetic cues modulating this metabolic switch remain largely undetermined. We identified a metabolic function for the promyelocytic leukemia (PML) gene, uncovering an unexpected role for this bona fide tumor suppressor in breast cancer cell survival. We found that PML acted as both a negative regulator of PPAR? coactivator 1A (PGC1A) acetylation and a potent activator of PPAR signaling and fatty acid oxidation. We further showed that PML promoted ATP production and inhibited anoikis. Importantly, PML expression allowed luminal filling in 3D basement membrane breast culture models, an effect that was reverted by the pharmacological inhibition of fatty acid oxidation. Additionally, immunohistochemical analysis of breast cancer biopsies revealed that PML was overexpressed in a subset of breast cancers and enriched in triple-negative cases. Indeed, PML expression in breast cancer correlated strikingly with reduced time to recurrence, a gene signature of poor prognosis, and activated PPAR signaling. These findings have important therapeutic implications, as PML and its key role in fatty acid oxidation metabolism are amenable to pharmacological suppression, a potential future mode of cancer prevention and treatment.
Sirt3 is a mitochondrial sirtuin, predominantly expressed in highly metabolic tissues. Germline ablation of Sirt3 has major metabolic consequences, including increased susceptibility to metabolic damage and oxidative stress after high fat feeding. In order to determine the contribution of liver and skeletal muscle to these phenotypes, we generated muscle-specific Sirt3 (Sirt3(skm-/-)) and liver-specific Sirt3 (Sirt3(hep-/-)) knock-out mice. Despite a marked global hyperacetylation of mitochondrial proteins, Sirt3(skm-/-) and Sirt3(hep-/-) mice did not manifest any overt metabolic phenotype under either chow or high fat diet conditions. Similarly, there was no evidence for increased oxidative stress in muscle or liver when Sirt3 was ablated in a tissue-specific manner. These observations suggest that the mitochondrial hyperacetylation induced by Sirt3-deletion in a tissue specific manner is not necessarily linked to mitochondrial dysfunction and does not recapitulate the metabolic abnormalities observed in the germline Sirt3 knock-out mice.
Decremental loss of PTEN results in cancer susceptibility and tumor progression. PTEN elevation might therefore be an attractive option for cancer prevention and therapy. We have generated several transgenic mouse lines with PTEN expression elevated to varying levels by taking advantage of bacterial artificial chromosome (BAC)-mediated transgenesis. The "Super-PTEN" mutants are viable and show reduced body size due to decreased cell number, with no effect on cell size. Unexpectedly, PTEN elevation at the organism level results in healthy metabolism characterized by increased energy expenditure and reduced body fat accumulation. Cells derived from these mice show reduced glucose and glutamine uptake and increased mitochondrial oxidative phosphorylation and are resistant to oncogenic transformation. Mechanistically we find that PTEN elevation orchestrates this metabolic switch by regulating PI3K-dependent and -independent pathways and negatively impacting two of the most pronounced metabolic features of tumor cells: glutaminolysis and the Warburg effect.
Lactate is an important marker for anaerobic glucose metabolism, and it is therefore of particular interest in, for example, cerebral ischemia, skeletal muscle disorders, and in the monitoring of oncology treatments. However, the in vivo detection of lactate with magnetic resonance spectroscopy is complicated by the overlap of the low-intensity lactate methyl resonance with lipid signal. Therefore, double-quantum filters have been employed to dephase the overlapping lipid signal, as they allow for a very high lipid suppression efficiency. For reliable lactate detection in lipid-rich environment, very large crushing gradients have to be employed to dephase the lipid signal under the noise level. Double-quantum filters are generally associated with signal loss of the metabolite of interest. For lactate, half of the signal is lost by selecting either the double- or the zero-quantum coherences. Moreover, owing to incomplete refocusing, traditional double-quantum filters with very large crusher gradients exhibit additional loss of the already low-lactate signal. In this study, a refocused double-quantum filter is described, which does not suffer from this source of additional signal loss. Therefore, it becomes possible to detect lactate at lower concentrations, or in lipid-rich environments. Lactate measurements are shown in the human calf muscle at 7 T.
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