No abstract

The rate of phosphocreatine (PCr) resynthesis following physical exercise, has been extensively studied with 31P-MRS. Previous studies have used small surface coils that were limited to measuring one superficial muscle per experiment. Our present work focuses on the development and implementation of a spectrally selective 3D turbo-spin-echo sequence at 3T and 7T with temporal resolution of 24s, using two geometrically identical volume coils. We acquired imaging data of PCr recovery from four healthy volunteers and one diabetic patient, who performed plantar flexions using resistance bands. We segmented the anatomical regions of six different muscles from the lower leg, namely the gastrocnemius (lateral and medial), the tibialis (anterior and posterior), the soleus and the peroneus and measured the local PCr resynthesis rate constants. During the same examination, we also acquired unlocalized 31P-MRS data at a temporal resolution of 6s. At 3T, the PCr resynthesis rate constants were measured at 25.4±3.7s (n=4, mean±standard deviation) using the MRS method and 25.6±4.4s using the MRI method. At 7T, the measured rates were 26.4±3.2s and 26.2±4.7s for MRS and MRI. Using our imaging method, we measured the local PCr resynthesis rate constants in six individual muscles of the lower leg (min/max 20.2/31.7s). The recovery rate constants measured for the diabetic patient were 55.5s (MRS) and 52.7s (MRI). The successful implementation of our 3D-method suggests that imaging is possible at both fields with relatively high spatial resolution (voxel size: 4.2 ml at 3T and 1.6 ml at 7T) using volume coils and that local PCr resynthesis rates can be obtained in a single measurement. The advantage of the imaging method is that it can highlight differences in PCr resynthesis rates between different muscles in a single measurement in order to study spatial gradients of metabolic properties of diseased states for which very little is currently known.

The rate of phosphocreatine (PCr) resynthesis following physical exercise is an accepted index of mitochondrial oxidative metabolism and has been studied extensively with unlocalized 31P-MRS methods and small surface coils. Imaging experiments using volume coils that measure several muscles simultaneously can provide new insights into the variability of muscle function in healthy and diseased states. However, they are limited by long acquisition times relative to the dynamics of PCr recovery. This work focuses on the implementation of a compressed sensing (CS) technique to accelerate imaging of PCr resynthesis following physical exercise, using a modified 3D turbo-spin-echo sequence and principal component analysis (PCA) as sparsifying transform. The CS technique was initially validated using 2-fold retrospective undersampling of fully-sampled data from four volunteers acquired on a 7T MRI system (voxel size: 1.6 ml, temporal resolution: 24 s), which led to an accurate estimation of the mono-exponential PCr resynthesis rate constant (mean error < 6.4%). Acquisitions with prospective 2-fold acceleration (temporal resolution: 12 s) demonstrated that 3D mapping of PCr resynthesis is possible at a temporal resolution that is sufficiently high for characterizing the recovery curve of several muscles in a single measurement.

The development of chemical exchange saturation transfer (CEST) has led to the establishment of new contrast mechanisms in magnetic resonance imaging, which serve as enablers for advanced molecular imaging strategies. Macromolecules in tissues and organs often give rise to broad and asymmetric exchange effects, called magnetization transfer (MT) effects, which can mask the CEST contrast of interest. We show here that the saturation of these macromolecular pools simultaneously at two distinct frequencies can level out the asymmetric MT effects, thus allowing one to isolate the CEST effects in vivo. For the first time, clean CEST contrast for glycosaminoglycans (gagCEST) in cartilage in the human knee joint is presented. In addition, the method allows one to clearly demarcate glycosaminoglycan measurements from cartilage and synovial fluid regions. This uniform-MT CEST methodology has wide applicability in in vivo molecular imaging (such as brain, skeletal muscle, etc).

Body fat distribution is a major, heritable risk factor for cardiometabolic disease, independent of overall adiposity. Using exome-sequencing in 618,375 individuals (including 160,058 non-Europeans) from the UK, Sweden and Mexico, we identify 16 genes associated with fat distribution at exome-wide significance. We show 6-fold larger effect for fat-distribution associated rare coding variants compared with fine-mapped common alleles, enrichment for genes expressed in adipose tissue and causal genes for partial lipodystrophies, and evidence of sex-dimorphism. We describe an association with favorable fat distribution (p = 1.8 × 10−09), favorable metabolic profile and protection from type 2 diabetes (~28% lower odds; p = 0.004) for heterozygous protein-truncating mutations in INHBE, which encodes a circulating growth factor of the activin family, highly and specifically expressed in hepatocytes. Our results suggest that inhibin βE is a liver-expressed negative regulator of adipose storage whose blockade may be beneficial in fat distribution-associated metabolic disease.