Intramyocellular Lipid Research Articles

Potential Utility of Electrical Impedance Myography in Evaluating Age-Related Skeletal Muscle Function Deficits.

Skeletal muscle function deficits associated with advancing age are due to several physiological and morphological changes including loss of muscle size and quality (conceptualized as a reduction in the intrinsic force-generating capacity of a muscle when adjusted for muscle size). Several factors can contribute to loss of muscle quality, including denervation, excitation-contraction uncoupling, increased fibrosis, and myosteatosis (excessive levels of inter- and intramuscular adipose tissue and intramyocellular lipids). These factors also adversely affect metabolic function. There is a major unmet need for tools to rapidly and easily assess muscle mass and quality in clinical settings with minimal patient and provider burden. Herein, we discuss the potential for electrical impedance myography (EIM) as a tool to evaluate muscle mass and quality in older adults. EIM applies weak, non-detectible (e.g., 400 μA), mutifrequency (e.g., 1 kHz–1 MHz) electrical currents to a muscle (or muscle group) through two excitation electrodes, and resulting voltages are measured via two sense electrodes. Measurements are fast (~5 s/muscle), simple to perform, and unaffected by factors such as hydration that may affect other simple measures of muscle status. After nearly 2 decades of study, EIM has been shown to reflect muscle health status, including the presence of atrophy, fibrosis, and fatty infiltration, in a variety of conditions (e.g., developmental growth and maturation, conditioning/deconditioning, and obesity) and neuromuscular diseases states [e.g., amyotrophic lateral sclerosis (ALS) and muscular dystrophies]. In this article, we describe prior work and current evidence of EIM’s potential utility as a measure of muscle health in aging and geriatric medicine.

The Effect of Obstructive Sleep Apnea and Continuous Positive Airway Pressure Therapy on Skeletal Muscle Lipid Content in Obese and Nonobese Men.

Obstructive sleep apnea (OSA), independently of obesity (OBS), predisposes to insulin resistance (IR) for largely unknown reasons. Because OSA-related intermittent hypoxia triggers lipolysis, overnight increases in circulating free fatty acids (FFAs) including palmitic acid (PA) may lead to ectopic intramuscular lipid accumulation potentially contributing to IR. Using 3-T-1H-magnetic resonance spectroscopy, we therefore compared intramyocellular and extramyocellular lipid (IMCL and EMCL) in the vastus lateralis muscle at approximately 7 am between 26 male patients with moderate-to-severe OSA (17 obese, 9 nonobese) and 23 healthy male controls (12 obese, 11 nonobese). Fiber type composition was evaluated by muscle biopsies. Moreover, we measured fasted FFAs including PA, glycated hemoglobin A1c, thigh subcutaneous fat volume (ScFAT, 1.5-T magnetic resonance tomography), and maximal oxygen uptake (VO2max). Fourteen patients were reassessed after continuous positive airway pressure (CPAP) therapy. Total FFAs and PA were significantly (by 178% and 166%) higher in OSA patients vs controls and correlated with the apnea-hypopnea index (AHI) (r ≥ 0.45, P < .01). Moreover, IMCL and EMCL were 55% (P < .05) and 40% (P < .05) higher in OSA patients, that is, 114% and 103% in nonobese, 24.4% and 8.4% in obese participants (with higher control levels). Overall, PA, FFAs (minus PA), and ScFAT significantly contributed to IMCL (multiple r = 0.568, P = .002). CPAP significantly decreased EMCL (–26%) and, by trend only, IMCL, total FFAs, and PA. Muscle fiber composition was unaffected by OSA or CPAP. Increases in IMCL and EMCL are detectable at approximately 7 am in OSA patients and are partly attributable to overnight FFA excesses and high ScFAT or body mass index. CPAP decreases FFAs and IMCL by trend but significantly reduces EMCL.

Imaging Evaluation of Fat Infiltration in Paraspinal Muscles on MRI: A Systematic Review with a Focus on Methodology.

PurposeNumerous studies have applied a variety of methods to assess paraspinal muscle degeneration. However, the methodological differences in imaging evaluation may lead to imprecise or inconsistent results. This article aimed to provide a pragmatic summary review of the current imaging modalities, measurement protocols, and imaging parameters in the evaluation of paraspinal muscle fat infiltration (FI) in MRI studies.MethodsWeb of Science, EMBASE, and PubMed were searched from January 2005 to March 2020 to identify studies that examined the FI of paraspinal muscles on MRI among patients with lumbar degenerative diseases.ResultsIntramyocellular lipids measured by magnetic resonance spectroscopy and FI measured by chemical‐shift MRI were both correlated to low back pain and several degenerative lumbar diseases, whereas results on the relationship between FI and degenerative lumbar pathologies using conventional MRI were conflicting. Multi‐segment measurement of FI at the lesion segment and adjacent segments could be a prognostic indicator for lumbar surgery. Most studies adopted the center of the intervertebral disc or endplate as the level of slice to evaluate the FI. Compared with visual semiquantitative assessment, quantitative parameters appeared to be precise for eliminating individual or modality differences. It has been demonstrated that fat CSA/total CSA (based on area) and muscle–fat index (based on signal intensity) as quantitative FI parameters are associated with multiple lumbar diseases and clinical outcomes after surgery.ConclusionHaving a good command of the methodology of paraspinal muscle FI on MRI was effective for diagnosis and prognosis in clinical practice.

Empagliflozin Lowers Mitochondrial Respiration and Skeletal Muscle Sphingolipid Content in Female Mice Fed Western Diet

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a frontline treatment for type 2 diabetes due to their ability to attenuate hyperglycemia (via glucosuria). Mounting evidence indicates SGLT2 inhibitors can also alter mitochondrial metabolism, enhance reliance upon fat oxidation and attenuate fat accumulation in a growing list of tissues. Nevertheless, the impact of SGLT2 inhibition on skeletal muscle remains largely unexplored. The objective of this study was to test the hypothesis that SGLT2 inhibition would promote enhanced mitochondrial capacity for fat oxidation and lower accumulation of harmful lipids in skeletal muscle of diet-induced obese mice. Female C57BL/6J mice, aged 26 weeks, were provided ad libitum access to either low-fat diet (LFD, n=9) or western diet (WD) for 8-weeks. WD mice were then randomized to 4-weeks of diet supplemented with 10mg/kg (0.01%) empagliflozin (WD+Emp, n=10) or untreated control (WD, n = 10). Dual-energy x-ray absorptiometry and glucose tolerance tests were performed in all groups pre- and post-empagliflozin treatment. At week 12, mitochondria were isolated from quadriceps muscle and measured by high-resolution respirometry using octanoyl-carnitine+malate (OCM) and other non-lipid substrates. Intramyocellular lipids were assessed using liquid chromatography, tandem mass spectrometry. As expected, WD mice had greater body weight and fat mass, as well as impaired glucose tolerance, when compared with LFD mice (all P<0.05). Four weeks of empagliflozin treatment improved glucose tolerance in WD+Emp mice (P<0.01 for week 12 vs. 8), despite no differences in body weight or fat mass compared with pre-treatment (both P>0.05 for week 12 vs. 8). Lipid-supported mitochondrial respiration and overall lipid content (e.g., triacylglycerols, select sphingolipids and ceramides) were greater in skeletal muscle from WD compared with LFD mice (all comparisons P<0.05). Such effects of WD on muscle lipid metabolism were largely reversed with empagliflozin treatment. There was overall main effect of lower mitochondrial respiration in WD+Emp compared with WD (P<0.001), and a tendency for lower concentration of numerous sphingolipid and ceramide species (mean difference = 9-34%). We interpret this as preliminary evidence that empagliflozin can reverse some WD-induced adaptations to skeletal muscle lipid metabolism, which may contribute to the improvement in glucose control.

A High-Fat Diet Aggravates the Age-Related Decline in Skeletal Muscle Structure and Function.

The age-related decline in muscle function is aggravated by a high-fat diet (HFD)-induced increase in fat mass. The hypothesis is that an HFD leads to a faster accumulation of intramyocellular lipids (IMCL) and an earlier onset of muscle dysfunction in old than in young-adult individuals. The IMCL accumulation is attenuated in young-adult organisms by an elevated oxidative capacity. Methionine restriction enhances mitochondrial biogenesis and is promising to combat obesity across the ages.

Branched-Chain Amino Acid Supplementation Does Not Preserve Lean Mass or Affect Metabolic Profile in Adults with Overweight or Obesity in a Randomized Controlled Weight Loss Intervention

Branched-chain amino acid (BCAA) supplementation has been shown to increase muscle mass or prevent muscle loss during weight loss. We aimed to investigate the effects of a BCAA-supplemented hypocaloric diet on lean mass preservation and insulin sensitivity. A total of 132 Chinese adults (63 men and 69 women aged 21-45 y, BMI 25-36kg/m2) were block randomly assigned by gender and BMI into 3 hypocaloric diet (deficit of 500kcal/d) groups: standard-protein (14%) with placebo (control, CT) or BCAA supplements at 0.1g·kg-1 body weight·d-1 (BCAA) or high-protein (27%) with placebo (HP). The subjects underwent 16 wk of dietary intervention with provision of meals and supplements, followed by 8 wk of weight maintenance with provision of supplements only. One-way ANOVA analysis was conducted to analyze the primary (lean mass and insulin sensitivity) and secondary outcomes (anthropometric and metabolic parameters) among the 3 groups. Paired t-test was used to analyze the change in each group. The 3 groups demonstrated similar significant reductions in body weight (7.97%), fat mass (13.8%), and waist circumference (7.27%) after 16 wk of energy deficit. Lean mass loss in BCAA (4.39%) tended to be lower than in CT (5.39%) and higher compared with HP (3.67%) (P=0.06). Calf muscle volume increased 3.4% in BCAA and intramyocellular lipids (IMCLs) decreased in BCAA (17%) and HP (18%) (P<0.05) over 16 wk. During the 8 wk weight maintenance period, lean mass gain in BCAA (1.03%) tended to be lower compared with CT (1.58%) and higher than in HP (-0.002%) (P=0.04). Lean mass gain differed significantly between CT and HP (P=0.03). Insulin sensitivity and metabolic profiles did not differ among the groups throughout the study period. BCAA supplementation does not preserve lean mass or affect insulin sensitivity in overweight and obese adults during weight loss. A higher protein diet may be more advantageous for lean mass preservation.

Two weeks of single-leg immobilization alters intramyocellular lipid storage characteristics in healthy, young women.

Muscle disuse rapidly induces insulin resistance (IR). Despite a relationship between intramyocellular lipid (IMCL) content and IR, during muscle-disuse IR develops before IMCL accumulation, suggesting that IMCL are not related to disuse-induced IR. However, recent studies show that it is not total IMCL content, but IMCL size and location that are related to IR. Changes in these IMCL parameters may occur prior to increases in IMCL content, thus contributing to disuse-induced IR. Omega-3 fatty acids may mitigate the effects of disuse on IR by preventing a decline in insulin signaling proteins. Twenty women (age 22 ± 3 yr) received either 5 g·day-1 omega-3 fatty acid or isoenergetic sunflower oil for 4 wk prior to, throughout 2 wk of single-leg immobilization, and during 2 wk of recovery. Changes in IMCL characteristics and insulin signaling proteins were examined in vastus lateralis samples taken before supplementation and immobilization, and following immobilization and recovery. Omega-3 supplementation had no effect. IMCL area density decreased in the subsarcolemmal region during immobilization and recovery (-19% and -56%, respectively, P = 0.009). IMCL size increased in the central intermyofibrillar region during immobilization (43%, P = 0.007), returning to baseline during recovery. PLIN5 and AKT increased during immobilization (87%, P = 0.002; 30%, P = 0.007, respectively). PLIN 5 remained elevated and AKT increased further (15%) during recovery. IRS1, AS160, and GLUT4 decreased during immobilization (-35%, P = 0.001; -44%, P = 0.03; -56%, P = 0.02, respectively), returning to baseline during recovery. Immobilization alters IMCL storage characteristics while negatively affecting unstimulated insulin signaling protein content in young women.NEW & NOTEWORTHY We report that the subcellular storage location of IMCL is altered by limb immobilization, highlighting the need to evaluate IMCL storage location when assessing the effects of disuse on IMCL content. We also found that AKT content increased during immobilization in our female population, contrary to studies in males finding that AKT decreases during disuse, highlighting that men and women may respond differently to disuse and the necessity to include women in all research.

Dyslipidemia, Insulin Resistance, Ectopic Lipid Accumulation, and Vascular Function in Resistance to Thyroid Hormone β.

PurposeIn resistance to thyroid hormone due to mutations in thyroid hormone receptor β, peripheral tissues are variably refractory to the action of circulating thyroid hormones. We evaluated parameters contributing to atherosclerotic risk in this disorder.MethodsWe measured low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), nonesterified fatty acids (NEFA), intrahepatic lipid (IHL) and intramyocellular lipid (IMCL), Homeostasis-model assessment of insulin resistance (HOMA-IR), augmentation index (AIx) and pulse wave velocity (PWV), flow-mediated dilatation, and carotid intima-media thickness (cIMT) in an unselected, genetically confirmed cohort of adult RTHβ patients (n = 27-77) and compared these with measurements in healthy subjects (up to n = 100) and thyrotoxic patients (n = 40).ResultsResistance to thyroid hormone beta (RTHβ) patients exhibited higher LDL-C (P = 0.008) and TG (P = 0.002) and lower HDL-C concentrations (P = 0.015 × 10–2) than control subjects, with LDL-C being higher than in thyrotoxic patients with comparable hyperthyroxinemia. Proprotein convertase subtilisin/kexin 9 (P = 0.002) and apolipoprotein B (P = 0.0009) levels were reduced in thyrotoxic patients but not lower in RTHβ patients or control subjects. Intrahepatic lipid (P = 0.02 × 10–4), IMCL (P = 0.002), HOMA-IR (P = 0.01 × 10–2), and NEFA (P = 0.04 × 10–6) were significantly higher in RTHβ patients than control subjects. Flow-mediated dilatation was increased (P = 0.04) but cIMT (P = 0.71), PWV P = 0.81), and AIx (P = 0.95) were unaltered in RTHβ patients.ConclusionsWe have documented mixed dyslipidemia with hepatic and IMCL accumulation in RTHβ, suggesting that surveillance for these metabolic abnormalities is warranted. How they combine with enhanced endothelial function and unaltered vessel wall thickness and compliance to determine overall cardiometabolic risk in this disorder remains to be defined.

A 12-week aerobic exercise intervention results in improved metabolic function and lower adipose tissue and ectopic fat in high-fat diet fed rats.

Investigations of long-term exercise interventions in humans to reverse obesity is expensive and is hampered by poor compliance and confounders. In the present study, we investigated intrahepatic and muscle fat, visceral and subcutaneous fat pads, plasma metabolic profile and skeletal muscle inflammatory markers in response to 12-week aerobic exercise in an obese rodent model. Six-week-old male Wistar rats (n=20) were randomized to chow-fed control (Control, n=5), sedentary high-fat diet (HFD, n=5), chow-fed exercise (Exercise, n=5) and HFD-fed exercise (HFD+Exercise, n=5) groups. The exercise groups were subjected to 12 weeks of motorized treadmill running at a speed of 18 m/min for 30 min/day. Differences in post-intervention measures were assessed by analysis of covariance (ANCOVA), adjusted for baseline bodyweight and pre-intervention measures, where available. Post-hoc analyses were performed with Bonferroni correction. Plasma metabolic profile was worsened and fat pads, ectopic fat in muscle and liver and inflammatory markers in skeletal muscle were elevated in sedentary HFD-fed animals relative to chow-fed controls. HFD+Exercise animals had significantly lower leptin (P=0.0004), triglycerides (P=0.007), homeostatic model assessment of insulin resistance (HOMA-IR; P=0.065), intramyocellular lipids (IMCLs; P=0.003), intrahepatic lipids (IHLs; P<0.0001), body fat% (P=0.001), subcutaneous adipose tissue (SAT; P<0.0001), visceral adipose (P<0.0001) and total fat mass (P<0.0001), relative to sedentary HFD-fed animals, despite only modestly lower bodyweight. Messenger RNA (mRNA) expression of inflammatory markers Interleukin 6 (IL6) and Tumor necrosis factor α (TNFα) were also reduced with aerobic exercise in skeletal muscle. Our results suggest that 12 weeks of aerobic exercise training is effective in improving metabolic health, fat depots, ectopic fat and inflammation even against a high-fat dietary background.

Systemic oxidative stress is associated with lower aerobic capacity and impaired skeletal muscle energy metabolism in heart failure patients

Oxidative stress plays a role in the progression of chronic heart failure (CHF). We investigated whether systemic oxidative stress is linked to exercise intolerance and skeletal muscle abnormalities in patients with CHF. We recruited 30 males: 17 CHF patients, 13 healthy controls. All participants underwent blood testing, cardiopulmonary exercise testing, and magnetic resonance spectroscopy (MRS). The serum thiobarbituric acid reactive substances (TBARS; lipid peroxides) were significantly higher (5.1 ± 1.1 vs. 3.4 ± 0.7 μmol/L, p < 0.01) and the serum activities of superoxide dismutase (SOD), an antioxidant, were significantly lower (9.2 ± 7.1 vs. 29.4 ± 9.7 units/L, p < 0.01) in the CHF cohort versus the controls. The oxygen uptake (VO2) at both peak exercise and anaerobic threshold was significantly depressed in the CHF patients; the parameters of aerobic capacity were inversely correlated with serum TBARS and positively correlated with serum SOD activity. The phosphocreatine loss during plantar-flexion exercise and intramyocellular lipid content in the participants' leg muscle measured by 31phosphorus- and 1proton-MRS, respectively, were significantly elevated in the CHF patients, indicating abnormal intramuscular energy metabolism. Notably, the skeletal muscle abnormalities were related to the enhanced systemic oxidative stress. Our analyses revealed that systemic oxidative stress is related to lowered whole-body aerobic capacity and skeletal muscle dysfunction in CHF patients.

Increasing skeletal muscle carnitine content in older individuals increases whole-body fat oxidation during moderate-intensity exercise.

Intramyocellular lipid (IMCL) utilization is impaired in older individuals, and IMCL accumulation is associated with insulin resistance. We hypothesized that increasing muscle total carnitine content in older men would increase fat oxidation and IMCL utilization during exercise, and improve insulin sensitivity. Fourteen healthy older men (69 ± 1 year, BMI 26.5 ± 0.8 kg/m2) performed 1 h of cycling at 50% VO2max and, on a separate occasion, underwent a 60 mU/m2/min euglycaemic hyperinsulinaemic clamp before and after 25 weeks of daily ingestion of a 220 ml insulinogenic beverage (44.4 g carbohydrate, 13.8 g protein) containing 4.5 g placebo (n = 7) or L‐carnitine L‐tartrate (n = 7). During supplementation, participants performed twice‐weekly cycling for 1 h at 50% VO2max. Placebo ingestion had no effect on muscle carnitine content or total fat oxidation during exercise at 50% VO2max. L‐carnitine supplementation resulted in a 20% increase in muscle total carnitine content (20.1 ± 1.2 to 23.9 ± 1.7 mmol/kg/dm; p < 0.01) and a 20% increase in total fat oxidation (181.1 ± 15.0 to 220.4 ± 19.6 J/kg lbm/min; p < 0.01), predominantly due to increased IMCL utilization. These changes were associated with increased expression of genes involved in fat metabolism (ACAT1, DGKD & PLIN2; p < 0.05). There was no change in resting insulin‐stimulated whole‐body or skeletal muscle glucose disposal after supplementation. This is the first study to demonstrate that a carnitine‐mediated increase in fat oxidation is achievable in older individuals. This warrants further investigation given reduced lipid turnover is associated with poor metabolic health in older adults.

Resveratrol-induced remodelling of myocellular lipid stores: A study in metabolically compromised humans.

In non‐athletes, insulin sensitivity correlates negatively with intramyocellular lipid (IMCL) content. In athletes, however, a pattern of benign IMCL storage exists, which is characterized by lipid storage in type I muscle fibres, in small and numerous lipid droplets (LDs) preferable coated with PLIN5, without affecting insulin sensitivity. Administration of resveratrol has been promoted for its beneficial effects on glucose homeostasis. We observed that 30 days of oral resveratrol administration (150 mg/day) in metabolically compromised individuals showed a 33% increase in IMCL (placebo vs. resveratrol; 0.86 ± 0.090 AU vs. 1.14 ± 0.11 AU, p = 0.003) without impeding insulin sensitivity. Thus, the aim of the present study was to examine if a resveratrol‐mediated increase in IMCL content, in metabolically compromised individuals, changes the LD phenotype towards the phenotype we previously observed in athletes. For this, we studied IMCL, LD number, LD size, subcellular distribution and PLIN5 coating in different fibre types using high‐resolution confocal microscopy. As proof of concept, we observed a 2.3‐fold increase (p = 0.038) in lipid accumulation after 48 h of resveratrol incubation in cultured human primary muscle cells. In vivo analysis showed that resveratrol‐induced increase in IMCL is predominantly in type I muscle fibres (placebo vs. resveratrol; 0.97 ± 0.16% vs. 1.26 ± 0.09%; p = 0.030) in both the subsarcolemmal (p = 0.016) and intermyofibrillar region (p = 0.026) and particularly in PLIN5‐coated LDs (p = 0.024). These data indicate that administration of resveratrol augments IMCL content in metabolically compromised individuals towards a LD phenotype that mimics an ‘athlete like phenotype’.

Endurance Runners with Intramyocellular Lipid Accumulation and High Insulin Sensitivity Have Enhanced Expression of Genes Related to Lipid Metabolism in Muscle.

Context: Endurance-trained athletes have high oxidative capacities, enhanced insulin sensitivities, and high intracellular lipid accumulation in muscle. These characteristics are likely due to altered gene expression levels in muscle. Design and setting: We compared intramyocellular lipid (IMCL), insulin sensitivity, and gene expression levels of the muscle in eight nonobese healthy men (control group) and seven male endurance athletes (athlete group). Their IMCL levels were measured by proton-magnetic resonance spectroscopy, and their insulin sensitivity was evaluated by glucose infusion rate (GIR) during a euglycemic–hyperinsulinemic clamp. Gene expression levels in the vastus lateralis were evaluated by quantitative RT-PCR (qRT-PCR) and microarray analysis. Results: IMCL levels in the tibialis anterior muscle were approximately 2.5 times higher in the athlete group compared to the control group, while the IMCL levels in the soleus muscle and GIR were comparable. In the microarray hierarchical clustering analysis, gene expression patterns were not clearly divided into control and athlete groups. In a gene set enrichment analysis with Gene Ontology gene sets, “RESPONSE TO LIPID” was significantly upregulated in the athlete group compared with the control group. Indeed, qRT-PCR analysis revealed that, compared to the control group, the athlete group had 2–3 times higher expressions of proliferator-activated receptor gamma coactivator-1 alpha (PGC1A), adiponectin receptors (AdipoRs), and fatty acid transporters including fatty acid transporter-1, plasma membrane-associated fatty acid binding protein, and lipoprotein lipase. Conclusions: Endurance runners with higher IMCL levels have higher expression levels of genes related to lipid metabolism such as PGC1A, AdipoRs, and fatty acid transporters in muscle.

Effect of a Low-Fat Vegan Diet on Body Weight, Insulin Sensitivity, Postprandial Metabolism, and Intramyocellular and Hepatocellular Lipid Levels in Overweight Adults

Excess body weight and insulin resistance lead to type 2 diabetes and other major health problems. There is an urgent need for dietary interventions to address these conditions. To measure the effects of a low-fat vegan diet on body weight, insulin resistance, postprandial metabolism, and intramyocellular and hepatocellular lipid levels in overweight adults. This 16-week randomized clinical trial was conducted between January 2017 and February 2019 in Washington, DC. Of 3115 people who responded to flyers in medical offices and newspaper and radio advertisements, 244 met the participation criteria (age 25 to 75 years; body mass index of 28 to 40) after having been screened by telephone. Participants were randomized in a 1:1 ratio. The intervention group (n = 122) was asked to follow a low-fat vegan diet and the control group (n = 122) to make no diet changes for 16 weeks. At weeks 0 and 16, body weight was assessed using a calibrated scale. Body composition and visceral fat were measured by dual x-ray absorptiometry. Insulin resistance was assessed with the homeostasis model assessment index and the predicted insulin sensitivity index (PREDIM). Thermic effect of food was measured by indirect calorimetry over 3 hours after a standard liquid breakfast (720 kcal). In a subset of participants (n = 44), hepatocellular and intramyocellular lipids were quantified by proton magnetic resonance spectroscopy. Repeated measure analysis of variance was used for statistical analysis. Among the 244 participants in the study, 211 (87%) were female, 117 (48%) were White, and the mean (SD) age was 54.4 (11.6) years. Over the 16 weeks, body weight decreased in the intervention group by 5.9 kg (95% CI, 5.0-6.7 kg; P < .001). Thermic effect of food increased in the intervention group by 14.1% (95% CI, 6.5-20.4; P < .001). The homeostasis model assessment index decreased (-1.3; 95% CI, -2.2 to -0.3; P < .001) and PREDIM increased (0.9; 95% CI, 0.5-1.2; P < .001) in the intervention group. Hepatocellular lipid levels decreased in the intervention group by 34.4%, from a mean (SD) of 3.2% (2.9%) to 2.4% (2.2%) (P = .002), and intramyocellular lipid levels decreased by 10.4%, from a mean (SD) of 1.6 (1.1) to 1.5 (1.0) (P = .03). None of these variables changed significantly in the control group over the 16 weeks. The change in PREDIM correlated negatively with the change in body weight (r = -0.43; P < .001). Changes in hepatocellular and intramyocellular lipid levels correlated with changes in insulin resistance (both r = 0.51; P = .01). A low-fat plant-based dietary intervention reduces body weight by reducing energy intake and increasing postprandial metabolism. The changes are associated with reductions in hepatocellular and intramyocellular fat and increased insulin sensitivity. ClinicalTrials.gov Identifier: NCT02939638.

Skeletal Muscle Magnetic Resonance Biomarkers in GNE Myopathy.

To characterize muscle involvement and evaluate disease severity in patients with GNE myopathy using skeletal muscle MRI and proton magnetic resonance spectroscopy (1H-MRS). Skeletal muscle imaging of the lower extremities was performed in 31 patients with genetically confirmed GNE myopathy, including T1-weighted and short tau inversion recovery (STIR) images, T1 and T2 mapping, and 1H-MRS. Measures evaluated included longitudinal relaxation time (T1), transverse relaxation time (T2), and 1H-MRS fat fraction (FF). Thigh muscle volume was correlated with relevant measures of strength, function, and patient-reported outcomes. The cohort was representative of a wide range of disease progression. Contractile thigh muscle volume ranged from 5.51% to 62.95% and correlated with thigh strength (r = 0.91), the 6-minute walk test (r = 0.82), the adult myopathy assessment tool (r = 0.83), the activities-specific balance confidence scale (r = 0.65), and the inclusion body myositis functional rating scale (r = 0.62). Four stages of muscle involvement were distinguished by qualitative (T1W and STIR images) and quantitative methods: stage I: unaffected muscle (T1 = 1,033 ± 74.2 ms, T2 = 40.0 ± 1.9 ms, FF = 7.4 ± 3.5%); stage II: STIR hyperintense muscle with minimal or no fat infiltration (T1 = 1,305 ± 147 ms, T2 = 50.2 ± 3.5 ms, FF = 27.6 ± 12.7%); stage III: fat infiltration and STIR hyperintensity (T1 = 1,209 ± 348 ms, T2 = 73.3 ± 12.6 ms, FF = 57.5 ± 10.6%); and stage IV: complete fat replacement (T1 = 318 ± 39.9 ms, T2 = 114 ± 21.2 ms, FF = 85.6 ± 4.2%). 1H-MRS showed a significant decrease in intramyocellular lipid and trimethylamines between stage I and II, suggesting altered muscle metabolism at early stages. MRI biomarkers can monitor muscle involvement and determine disease severity noninvasively in patients with GNE myopathy. NCT01417533.

Current perspectives on obesity and skeletal muscle contractile function in older adults.

Obesity has become one of the most pressing public health issues of the 21st century and currently affects a substantial proportion of the older adult population. Although the cardiometabolic complications are well documented, research from the past 20 years has drawn attention to the detrimental effects of obesity on physical performance in older adults. Obesity-related declines in physical performance are due, in part, to compromised muscle strength and power. Recent evidence suggests there are a number of mechanisms potentially underlying reduced whole muscle function, including alterations in myofilament protein function and cellular contractile properties, and these may be related to morphological adaptations, such as shifts in fiber type composition and increased intramyocellular lipid content within skeletal muscle. To date, even less research has focused on how exercise and weight loss interventions for obese older adults affect these mechanisms. In light of this work, we provide an update on the current knowledge related to obesity and skeletal muscle contractile function and highlight a number of questions to address potential etiologic mechanisms as well as intervention strategies, which may help advance our understanding of how physical performance can be improved among obese older adults.

Impaired insulin sensitivity and carbohydrate oxidation during bed rest in healthy participants

Rationale: Immobilisation reduces insulin-mediated whole body glucose disposal (GD) (1). The rate of decline of insulin stimulated GD and changes in carbohydrate (CHO) oxidation over the acute to chronic bed rest (BR) setting remain to be fully elucidated, as do to the physiological drivers of these events under conditions where energy balance is maintained. We, therefore, determined whole body GD, CHO oxidation and intramyocellular lipid (IMCL) content during acute and chronic BR whilst maintaining energy balance.

Decoration of myocellular lipid droplets with perilipins as a marker for in vivo lipid droplet dynamics: A super-resolution microscopy study in trained athletes and insulin resistant individuals

In many different cell types neutral lipids can be stored in lipid droplets (LDs). Nowadays, LDs are viewed as dynamic organelles, which store and release fatty acids depending on energy demand (LD dynamics). Proteins like perilipin 2 (PLIN2) and PLIN5 decorate the LD membrane and are determinants of LD lipolysis and fat oxidation, thus affecting LD dynamics. Trained athletes and type 2 diabetes (T2D) patients both have high levels of intramyocellular lipid (IMCL). While IMCL content scales negatively with insulin resistance, athletes are highly insulin sensitive in contrast to T2D patients, the so-called athlete's paradox. Differences in LD dynamics may be an underlying factor explaining the athlete's paradox. We aimed to quantify PLIN2 and PLIN5 content at individual LDs as a reflection of the ability to switch between fatty acid release and storage depending on energy demand. Thus, we developed a novel fluorescent super-resolution microscopy approach and found that PLIN2 protein abundance at the LD surface was higher in T2D patients than in athletes. Localization of adipocyte triglyceride lipase (ATGL) to the LD surface was lower in LDs abundantly decorated with PLIN2. While PLIN5 abundance at the LD surface was similar in athletes and T2D patients, we have observed previously that the number of PLIN5 decorated LDs was higher in athletes, indicating more LDs in close association with mitochondria. Thus, in athletes interaction of LDs with mitochondria was more pronounced and LDs have the protein machinery to be more dynamic, while in T2D patients the LD pool is more inert. This observation contributes to our understanding of the athlete's paradox.

Magnetic Resonance Spectroscopic Analysis of Multifidus Muscle Lipid Contents and Association with Nociceptive Pain in Chronic Low Back Pain.

Study DesignCross-sectional study.PurposeThis study aimed to analyze the differences in the lipid contents in chronic low back pain (CLBP) patients with nociceptive pain (NocP) and neuropathic pain (NeP) using magnetic resonance spectroscopy (MRS) of the multifidus muscle (Mm).Overview of LiteratureEarly identification of the pain characteristics with CLBP is important because specific treatment approaches are required, depending on NocP and NeP.MethodsThe participants were 50 patients with CLBP (23 men and 27 women; mean age, 63.1±17.8 years; range, 41–79 years). We compared the Visual Analog Scale (VAS) scores, intramyocellular lipids (IMCLs) and extramyocellular lipids (EMCLs) of the Mm in NocP and NeP groups, as evaluated with the Japanese NeP screening questionnaire.ResultsThe patients were categorized into the NocP (n=32) and NeP (n=18) groups. The mean VAS score of the NocP group was 59.3±3.1 mm and that of the NeP group was 73.6±4.6 mm. The mean VAS score was significantly higher in the NeP group as compared to that in the NocP group (p<0.01). As per the analysis of covariance for the VAS score, the mean IMCL levels of the Mm in the NocP and NeP groups were 722.3 mmol/L (95% confidence interval [CI], 611.4–833.1) and 484.8 mmol/L (95% CI, 381.1–588.5), respectively. The mean IMCL level was significantly higher in the NocP group than in the NeP group (p<0.05). The mean EMCL levels of the Mm for the NocP and NeP groups were 6,022.9 mmol/L (95% CI, 4,510.6–7,535.2) and 5,558.1 mmol/L (95% CI, 4,298.3–6,817.9), respectively; however, the difference was not significant (p=0.72).ConclusionsThe results indicated an association between the IMCL level of the Mm and NocP. Our results suggest that MRS of the Mm might be beneficial for the assessment of CLBP as well as appropriate targeted analgesic therapies.

Docosahexaenoic and eicosapentaenoic fatty acids differentially regulate glucose and fatty acid metabolism in L6 rat skeletal muscle cells.

The objective of this study was to investigate whether the n-3 polyunsaturated fatty acids (PUFAs) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) can directly regulate glucose and fat metabolism in skeletal muscle besides exerting anti-inflammatory effects. To accomplish this, L6 skeletal muscle cells were treated with 50 µM of either DHA or EPA for 1, 3, and 5 days. Here, we report that basal and insulin-stimulated rates of glucose uptake, glycogen synthesis, protein kinase B (AKT), and glycogen synthase kinase 3 (GSK3) phosphorylation were not affected by DHA or EPA. However, glucose and palmitate oxidation were consistently elevated by DHA treatment, whereas EPA only increased this variable transiently. Similarly, only DHA caused significant and sustained increases in AMP-activated protein kinase (AMPK) phosphorylation and protein levels of carnitine-palmitoyl transferase-1b (CPT1b) and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) in skeletal muscle cells. DHA also caused a larger anti-inflammatory effect than EPA in these cells. In conclusion, besides exerting anti-inflammatory effects, DHA and EPA directly regulated glucose and fat metabolism in skeletal muscle cells, although DHA was more effective in doing so than EPA. Thus, by directly enhancing glucose and fat oxidation, DHA may increase glucose disposal and reduce intramyocellular lipid accumulation.