Galectin-3 promotes the adipogenic differentiation of PDGFRα+ cells and ectopic fat formation in regenerating muscle

Worldwide prevalence of obesity is associated with the increase of lifestyle-related diseases. The accumulation of intermuscular adipose tissue (IMAT) is considered a major problem whereby obesity leads to sarcopenia and metabolic disorders and thus is a promising target for treating these pathological conditions. However, whereas obesity-associated IMAT is suggested to originate from PDGFRα+ mesenchymal progenitors, processes underlying their adipogenesis remain largely unexplored. Here, we comprehensively investigated intra- and extracellular changes associated with these processes using single-cell RNA sequencing (scRNA-Seq) and mass spectrometry. Our scRNA-Seq analysis identified a small PDGFRα+ cell population in obese mice directed strongly toward adipogenesis. Proteomic analysis showed that the appearance of this cell population is accompanied by an increase in galectin-3 in interstitial environments, which was found to activate adipogenic PPARγ signals in PDGFRα+ cells. Moreover, IMAT formation during muscle regeneration was significantly suppressed in galectin-3 KO mice. Our findings, together with these multi-omics datasets, could unravel microenvironmental networks during muscle regeneration highlighting possible therapeutic targets against IMAT formation in obesity.

Skeletal muscle and intermuscular adipose tissue gene expression profiling identifies new biomarkers with prognostic significance for insulin resistance progression and intervention response

Although insulin resistance often leads to Type 2 Diabetes Mellitus (T2D), its early stages remain often unrecognized thus reducing the probability of successful prevention and intervention. Moreover, treatment efficacy is affected by the genetics of the individual patient. To identify potential candidate genes for the prediction of diabetes risk and intervention response we linked genetic expression profiles of human skeletal muscle and intermuscular adipose tissue (IMAT) to fasting glucose (FG) and glucose infusion rate (GIR). We found that genes with a strong association to these measures clustered into three distinct expression patterns. Their predictive values for insulin resistance varied strongly between muscle and IMAT. Moreover, we discovered that individual genetic expression based classifications may differ from those classifications based predominantly on clinical parameters indicating a potential incomplete patient stratification. Out of the 15 top hit candidate genes, we identified ST3GAL2, AASS, ARF1 and the transcription factor SIN3A as novel candidates for a refined diabetes risk and intervention response prediction. Our results confirm that disease progression and a successful intervention depend on individual genetics. We anticipate that our findings may lead to a better understanding and prediction of the individual diabetes risk and may help to develop individualized intervention strategies.

Investigation of the Relationship between the Mid_Thigh Adipose Tissue Distribution Measured by MRI and Serum Osteocalcin—A Sex-Based Approach

Osteocalcin, in its non-carboxylated form, has a positive effect on glucose metabolism. Additionally, osteocalcin levels are related to body composition, especially muscle mass. The relation to the distribution of different adipose tissue types, such as subcutaneous, intermuscular, and visceral adipose tissue, is unclear. This study aimed to investigate associations between serum osteocalcin and the distribution of subcutaneous and intermuscular adipose tissue of the mid-thigh. Furthermore, the influence of different training methods on osteocalcin levels was investigated. We performed adipose tissue quantification of subcutaneous adipose tissue (SAT) and intramuscular adipose tissue (IMAT) using MRI measurements of the mid-thigh in 128 volunteers (63 male/65 female). Laboratory analysis included blood lipid panel, serum insulin, adiponectin, and osteocalcin measurements. The main observation was a significant correlation of total serum osteocalcin (TOC) and the distribution of adipose tissue of the mid-thigh (SAT/(SAT + IMAT)) (cc = −0.29/p-value = 0.002), as well as the cross-sectional muscle area (MA), increasing with the weekly resistance training duration in males. Additionally, TOC (p-value = 0.01) and MA (p-value = 0.03) were negatively related to serum insulin. The significant relationship between TOC and SAT/(SAT + IMAT) is a new finding and confirms the negative influence of IMAT on glucose metabolism in a sex-specific approach. We could substantiate this by the negative relation of TOC with serum insulin.

The Metabolic Significance of Intermuscular Adipose Tissue: Is IMAT a Friend or a Foe to Metabolic Health?

Adipose tissues are not homogeneous and show site-specific properties. An elusive and understudied adipose tissue depot – most likely due to its limited accessibility – is the intermuscular adipose depot (IMAT). Adipose tissue is a pliable organ with the ability to adapt to its physiological context, yet whether that adaptation is harmful or beneficial in the IMAT depot remains to be explored in humans. Potential reasons for IMAT accumulation in humans being deleterious or beneficial include: 1) sex and related circulating hormone levels, 2) race and ethnicity and 3) lifestyle factors (e.g. diet and physical activity level). IMAT quantity <i>per se</i> may not be the driving factor in the etiology of insulin resistance and type 2 diabetes but rather the quality of the IMAT itself is the true puppeteer. Adipose tissue quality likely influences its secreted factors which are also likely to influence metabolism of surrounding tissues. The advent of molecular assessments such as RNAseq, ATACseq and DNA methylation at the single cell and single nuclei levels, as well as the potential for ultrasound-guided biopsies specifically for IMAT, will permit more sophisticated investigations of human IMAT and dramatically advance our understanding of this enigmatic adipose tissue.

The Metabolic Significance of Intermuscular Adipose Tissue: Is IMAT a Friend or a Foe to Metabolic Health?

Adipose tissues are not homogeneous and show site-specific properties. An elusive and understudied adipose tissue depot – most likely due to its limited accessibility – is the intermuscular adipose depot (IMAT). Adipose tissue is a pliable organ with the ability to adapt to its physiological context, yet whether that adaptation is harmful or beneficial in the IMAT depot remains to be explored in humans. Potential reasons for IMAT accumulation in humans being deleterious or beneficial include: 1) sex and related circulating hormone levels, 2) race and ethnicity and 3) lifestyle factors (e.g. diet and physical activity level). IMAT quantity <i>per se</i> may not be the driving factor in the etiology of insulin resistance and type 2 diabetes but rather the quality of the IMAT itself is the true puppeteer. Adipose tissue quality likely influences its secreted factors which are also likely to influence metabolism of surrounding tissues. The advent of molecular assessments such as RNAseq, ATACseq and DNA methylation at the single cell and single nuclei levels, as well as the potential for ultrasound-guided biopsies specifically for IMAT, will permit more sophisticated investigations of human IMAT and dramatically advance our understanding of this enigmatic adipose tissue.

Deep learning for automatic segmentation of thigh and leg muscles

Objective In this study we address the automatic segmentation of selected muscles of the thigh and leg through a supervised deep learning approach. Material and methods The application of quantitative imaging in neuromuscular diseases requires the availability of regions of interest (ROI) drawn on muscles to extract quantitative parameters. Up to now, manual drawing of ROIs has been considered the gold standard in clinical studies, with no clear and universally accepted standardized procedure for segmentation. Several automatic methods, based mainly on machine learning and deep learning algorithms, have recently been proposed to discriminate between skeletal muscle, bone, subcutaneous and intermuscular adipose tissue. We develop a supervised deep learning approach based on a unified framework for ROI segmentation. Results The proposed network generates segmentation maps with high accuracy, consisting in Dice Scores ranging from 0.89 to 0.95, with respect to “ground truth” manually segmented labelled images, also showing high average performance in both mild and severe cases of disease involvement (i.e. entity of fatty replacement). Discussion The presented results are promising and potentially translatable to different skeletal muscle groups and other MRI sequences with different contrast and resolution.

Associations Between Lipoprotein Subfractions and Area and Density of Abdominal Muscle and Intermuscular Adipose Tissue: The Multi-Ethnic Study of Atherosclerosis

Skeletal muscle quantity and quality decrease with older age, which is partly attributed to ectopic fat infiltration and has negative metabolic consequences. To inform efforts to preserve skeletal muscle with aging, a better understanding of biologic correlates of quantity and quality of muscle and intermuscular adipose tissue (IMAT) is needed. We used targeted lipidomics of lipoprotein subfractions among 947 Multi-Ethnic Study of Atherosclerosis participants to provide a detailed metabolic characterization of area and density of abdominal muscle and IMAT. Serum lipoprotein subfractions were measured at the first visit using 1H-Nuclear Magnetic Resonance spectroscopy. Muscle and IMAT area (cm2) and density (Hounsfield units) were estimated at visit 2 or 3 using computed tomography of the total abdominal, locomotion (psoas), and stabilization (paraspinal, oblique, rectus abdominis) muscles. We identified lipoprotein subfractions associated with body composition using linear regression adjusting for demographics, lifestyle, and multiple comparisons. Among 105 lipoprotein subfractions, 24 were associated with total muscle area (absolute standardized regression coefficient range: 0.07–0.10, p-values ≤ 0.002), whereas none were associated with total muscle density. When examining muscle subgroups, 25 lipoprotein subfractions were associated with stabilization muscle area, with associations strongest among the obliques. For total IMAT area, there were 27 significant associations with lipoprotein subfractions (absolute standardized regression coefficient range: 0.09–0.13, p-values ≤ 0.002). Specifically, 27 lipoprotein subfractions were associated with stabilization IMAT area, with associations strongest among the oblique and rectus abdominis muscles. For total IMAT density, there were 39 significant associations with lipoprotein subfractions (absolute standardized regression coefficient range: 0.10–0.19, p-values ≤ 0.003). Specifically, 28 and 33 lipoprotein subfractions were associated with IMAT density of locomotion and stabilization (statistically driven by obliques) muscles, respectively. Higher VLDL (cholesterol, unesterified cholesterol, phospholipids, triglycerides, and apolipoprotein B) and lower HDL (cholesterol and unesterified cholesterol) were associated with higher muscle area, higher IMAT area, and lower IMAT density. Several associations between lipoprotein subfractions and abdominal muscle area and IMAT area and density were strongest among the stabilization muscles, particularly the obliques, illustrating the importance of examining muscle groups separately. Future work is needed to determine whether the observed associations indicate a lipoprotein profile contributing to worse skeletal muscle with fat infiltration.

Weight loss and exercise differentially affect insulin sensitivity, body composition, cardiorespiratory fitness and muscle strength in older adults with obesity; a randomized controlled trial

Background Aging-related disease risk is exacerbated by obesity and physical inactivity. It is unclear how weight loss and increased activity improve risk in older adults. We aimed to determine the effects of diet-induced weight loss with and without exercise on insulin sensitivity, VO2peak, body composition, and physical function in older obese adults. Methods Physically inactive older (68.6 ± 4.5 years) obese (BMI 37.4 ± 4.9 kg/m 2) adults were randomized to: Health education control (HEC; n=25); Diet-induced weight loss (WL; n=31); or Weight loss and exercise (WLEX; n=28) for 6 months. Insulin sensitivity was measured by hyperinsulinemic euglycemic clamp, body composition by DXA and MRI, strength by isokinetic dynamometry, and VO2peak by graded exercise test. Results WLEX improved (p&lt;0.05) peripheral insulin sensitivity (+75 ± 103%) vs. HEC (+12 ± 67%); WL (+36 ± 47%) vs. HEC did not reach statistical significance. WLEX increased VO2peak (+7 ± 12%) vs. WL (-2 ± 24%), and prevented reductions in strength and lean mass induced by WL (p&lt;0.05). WLEX decreased abdominal adipose tissue (-16 ± 9%) vs. HEC (-3 ± 8%) and intermuscular adipose tissue (-15 ± 13 %) vs. both HEC (+9 ± 15%) and WL (+2 ± 11%) (p&lt;0.01). Conclusions Exercise with weight loss improved insulin sensitivity and VO2peak, decreased ectopic fat, and preserved lean mass and strength. Weight loss alone decreased lean mass and strength. Older adults intending to lose weight should perform regular exercise to promote cardiometabolic and functional benefits, which may not occur with calorie restriction-induced weight loss alone.

Once Weekly Whole-Body Electromyostimulation Enhances Muscle Quality in Men: Data of the Randomized Controlled Franconian Electromyostimulation and Golf Study

Whole-body electromyostimulation (WB-EMS) is commercially advertised as a time-efficient resistance-type exercise technology. Indeed, the commercial, non-medical setting applies 20 min of WB-EMS only once a week. However, this setting conflicts with the approved scientific approach of higher training frequencies. Using data from an ongoing study on WB-EMS and golf performance as a vehicle, we evaluate the effect of once weekly WB-EMS on changes of fatty muscle infiltration, as a crucial parameter of muscle quality. Fifty-four moderately physically active male amateur golfers 18–70 years old were randomly allocated to a WB-EMS (n = 27) with a standard setting of once weekly 20 min and a non-WB-EMS control group (CG, n = 27). Intermuscular adipose tissue (IMAT) volume and intrafascial muscle tissue (MT) volume per unit of intrafascial volume as determined by magnetic resonance imaging were used to characterize muscle quality. Intention to treat analysis with multiple imputation was applied. WB-EMS was conducted at the participants’ homes; thus, the attendance rate was close to 100%. After 16 weeks of intervention, we observed increases in volume-adjusted IMAT (p = 0.040) and decreases in MT (p = 0.206) in the CG. IMAT decreased in the WB-EMS group (p = 0.215), while MT increased significantly (p = 0.032). Of importance, group difference (i.e., “effects”) for intra-group changes in volume-adjusted IMAT (effect size: d´ = 0.66; p = 0.028) and MT (d´ = 0.70; p = 0.020) was significant for both parameters. Once weekly WB-EMS application significantly affects muscle quality of the mid-thigh in moderately active, healthy men 18–70 years old.