Intramyocellular Lipid Content Research Articles

Intermuscular Adipose Tissue Content and Intramyocellular Lipid Fatty Acid Saturation Are Associated with Glucose Homeostasis in Middle-Aged and Older Adults.

BackgroundInsulin resistance is associated with the higher content of intermuscular adipose tissue (IMAT) and the saturation of intramyocellular lipid (IMCL), but a paucity of data exist in humans. This study examined associations among IMAT content, IMCL saturation, and fasting glucose concentration in middle-aged and older adults with overweight or obesity.MethodsSeventy-five subjects (26 males, 49 females) were recruited and thigh muscle and IMAT were assessed using magnetic resonance imaging. Vastus lateralis tissue was acquired from a subset of nine subjects and IMCL content and saturation were assessed using nonlinear dual complex microscopy.ResultsThe characteristics of the 75 subjects were as follows: age 59±11 years, body mass index 30±5 kg/m2, fasting glucose concentration 5.2±0.5 mmol/L, fasting insulin concentration 12.2±7.3 µU/mL, fasting homeostatic model assessment of insulin resistance (HOMA-IR) 2.9±2.0 (mean±SD). IMAT to muscle tissue (MT) volume ratio was positively associated with the saturated fatty acid to unsaturated fatty acid ratio in IMCL. IMAT:MT was positively associated with fasting glucose concentration and HOMA-IR. IMCL saturation was positively associated with fasting glucose concentration while muscle cell area, IMCL area, and % IMCL in muscle cell were not associated with fasting glucose concentration.ConclusionThese results indicate that higher intermuscular fat content and IMCL saturation may impact fasting glucose concentration in middle-aged and older adults with overweight or obesity. The centralization of adipose tissue in the appendicular region of the body may promote insulin resistance.

Magnetic Resonance Imaging and Spectroscopy to Assess Leg Muscle Macrostructure and Microstructure in Healthy Older Women: A Feasibility Assessment

BackgroundAdvanced magnetic resonance (MR) scanning techniques, such as diffusion tensor imaging (DTI) and proton MR spectroscopy (1H-MRS) permit microstructural evaluation of water diffusivity and intramyocellular lipid content, respectively. We aimed to determine the feasibility of performing advanced MR scanning (proton density [PD] weighted imaging, DTI, and 1H-MRS) to evaluate properties of leg muscles in older women with respect to: (1) participant recruitment using three community-based strategies; (2) participant tolerance to the MRI scan acquisition protocol; and (3) scan acquisition and analyses protocols. MethodsRecruitment feasibility was evaluated based on the number of participants enrolled using various strategies. Participant tolerance was feasible if the scanning session was uninterrupted and image artifacts were absent. Optimal PD imaging, DTI, and 1H-MRS acquisition and analyses protocols were established. ResultsNine women (mean age = 71 years) were recruited over four months. The acquisition protocol was well tolerated by all participants. Adaptations were required for women with short stature and vertebral fracture risk. PD-weighted image analyses were improved by using the phased array uniformity enhancement filter to increase tissue contrast. ConclusionsIt is feasible to use a combination of MR scanning methods to evaluate muscle macrostructure and microstructure in the leg of older women. Our findings suggest that advanced MR scanning methods can be used for future studies interested in quantifying components of muscle structure in older women, but prospective studies are needed to confirm whether change in microstructure can be detected in response to an intervention.

Insulin resistance in type 2 diabetes youth relates to serum free fatty acids and muscle mitochondrial dysfunction

AimsInsulin resistance (IR) correlates with mitochondrial dysfunction, free fatty acids (FFAs), and intramyocellular lipid (IMCL) in adults with type 2 diabetes (T2D). We hypothesized that muscle IR would relate to similar factors in T2D youth. MethodsParticipants included 17 youth with T2D, 23 normal weight controls (LCs), and 26 obese controls (OBs) of similar pubertal stage and activity level. ResultsT2D and OB groups were of similar BMI. T2D youth were significantly more IR and had higher calf IMCL and serum FFA concentrations during hyperinsulinemia. ADP time constant (ADPTC), a blood-flow dependent mitochondrial function measure, was slowed and oxidative phosphorylation rates lower in T2D. In multiple linear regression of the entire cohort, lack of FFA suppression and longer ADPTC, but not IMCL or HbA1c, were independently associated with IR. ConclusionWe found that elevated FFAs and mitochondrial dysfunction are early abnormalities in relatively well-controlled youth with T2D.Further, post-exercise oxidative metabolism appears affected by reduced blood flow, and is not solely an inherent mitochondrial defect. Thus, lowering FFAs and improving mitochondrial function and blood flow may be potential treatment targets in youth with T2D.

Resveratrol as Add-on Therapy in Subjects With Well-Controlled Type 2 Diabetes: A Randomized Controlled Trial.

To determine whether resveratrol supplementation can improve insulin sensitivity and promote overall metabolic health on top of standard diabetes care. Seventeen subjects with well-controlled type 2 diabetes (T2D) were treated with placebo and 150 mg/day resveratrol (resVida) in a randomized double-blind crossover study for 30 days. The main outcome measure was insulin sensitivity by the hyperinsulinemic-euglycemic clamp technique. Hepatic and peripheral insulin sensitivity were not affected by resveratrol treatment. Intrahepatic lipid content also remained unaffected by resveratrol; however, the change in intrahepatic lipid content correlated negatively with plasma resveratrol levels (R = -0.68, P = 0.03). Intramyocellular lipid content increased in type 2 muscle fibers (P = 0.03), and systolic blood pressure tended to decrease (P = 0.09) upon resveratrol treatment. In addition, resveratrol significantly improved ex vivo mitochondrial function (state 3 and state U respiration upon malate with octanoyl-carnitine, P < 0.005). Intriguingly, a correlation was found between plasma levels of a metabolite of resveratrol (dihydroresveratrol) and the metformin dose used by the patients (R = 0.66, P = 0.005), suggesting an interaction between metformin and resveratrol. It could be speculated that the lack of a resveratrol-induced insulin-sensitizing effect is caused by this interaction. Resveratrol supplementation does not improve hepatic or peripheral insulin sensitivity. Our results question the generalized value of resveratrol as an add-on therapy in the treatment of T2D and emphasize the need to perform studies in drug-naive patients with T2D or subjects with prediabetes.

The impact of ageing, physical activity, and pre-frailty on skeletal muscle phenotype, mitochondrial content, and intramyocellular lipids in men.

BackgroundThe exact impact of ageing on skeletal muscle phenotype and mitochondrial and lipid content remains controversial, probably because physical activity, which greatly influences muscle physiology, is rarely accounted for. The present study was therefore designed to investigate the effects of ageing, physical activity, and pre‐frailty on skeletal muscle phenotype, and mitochondrial and intramyocellular lipid content in men.MethodsRecreationally active young adult (20–30 yo; YA); active (ACT) and sedentary (SED) middle‐age (50–65 yo; MA‐ACT and MA‐SED); and older (65 + yo; 65 + ACT and 65 + SED) and pre‐frail older (65 + PF) men were recruited. Muscle biopsies from the vastus lateralis were collected to assess, on muscle cross sections, muscle phenotype (using myosin heavy chain isoforms immunolabelling), the fibre type‐specific content of mitochondria (by quantifying the succinate dehydrogenase stain intensity), and the fibre type‐specific lipid content (by quantifying the Oil Red O stain intensity).ResultsOnly 65 + SED and 65 + PF displayed significantly lower overall and type IIa fibre sizes vs. YA. 65 + SED displayed a lower type IIa fibre proportion vs. YA. MA‐SED and 65 + SED displayed a higher hybrid type IIa/IIx fibre proportion vs. YA. Sedentary and pre‐frail, but not active, men displayed lower mitochondrial content irrespective of fibre type vs. YA. 65 + SED, but not 65 + ACT, displayed a higher lipid content in type I fibres vs. YA. Finally, mitochondrial content, but not lipid content, was positively correlated with indices of muscle function, functional capacity, and insulin sensitivity across all subjects.ConclusionsTaken altogether, our results indicate that ageing in sedentary men is associated with (i) complex changes in muscle phenotype preferentially affecting type IIa fibres; (ii) a decline in mitochondrial content affecting all fibre types; and (iii) an increase in lipid content in type I fibres. They also indicate that physical activity partially protects from the effects of ageing on muscle phenotype, mitochondrial content, and lipid accumulation. No skeletal specific muscle phenotype of pre‐frailty was observed.

Consequences of Late-Stage Non–Small-Cell Lung Cancer Cachexia on Muscle Metabolic Processes

IntroductionThe loss of muscle is common in patients with advanced non–small-cell lung cancer (NSCLC) and contributes to the high morbidity and mortality of this group. The exact mechanisms behind the muscle loss are unclear. Patients and MethodsTo investigate this, 4 patients with stage IV NSCLC who met the clinical definitions for sarcopenia and cachexia were recruited, along with 4 age-matched healthy volunteers. After an overnight fast, biopsy specimens were obtained from the vastus lateralis, and the key components associated with inflammation and the control of muscle protein, carbohydrate, and fat metabolism were assessed. ResultsCompared with the healthy volunteers, significant increases in mRNA levels for interleukin-6 and NF-κB signaling and lower intramyocellular lipid content in slow-twitch fibers were observed in NSCLC patients. Although a significant decrease in phosphorylation of the mechanistic target of rapamycin (mTOR) signaling protein 4E-BP1 (Ser65) was observed, along with a trend toward reduced p70 S6K (Thr389) phosphorylation (P = .06), no difference was found between groups for the mRNA levels of MAFbx (muscle atrophy F box) and MuRF1 (muscle ring finger protein 1), chymotrypsin-like activity of the proteasome, or protein levels of multiple proteasome subunits. Moreover, despite decreases in intramyocellular lipid content, no robust changes in mRNA levels for key proteins involved in insulin signaling, glycolysis, oxidative metabolism, or fat metabolism were observed. ConclusionThese findings suggest that examining the contribution of suppressed mTOR signaling in the loss of muscle mass in late-stage NSCLC patients is warranted and reinforces our need to understand the potential contribution of impaired fat metabolism and muscle protein synthesis in the etiology of cancer cachexia.

Deep subcutaneous adipose tissue lipid unsaturation associates with intramyocellular lipid content

BackgroundObese twins have lower saturated and higher long-chain polyunsaturated fatty acids (FA) in subcutaneous adipose tissue (SAT) compared to their lean monozygotic (MZ) co-twin. Whether this holds for metabolically distinct deep (DSAT) and superficial (SSAT) depots is unknown. Here we use non-invasive magnetic resonance spectroscopy (MRS) to measure the FA unsaturation in body mass index (BMI) discordant MZ twins in DSAT and SSAT and their relationship to ectopic fat content and body fat distribution. The main finding is further confirmed in an independent cohort using standardized measurement times. MethodsMRS and magnetic resonance imaging were used to measure DSAT and SSAT unsaturation and their relationship to intramyocellular lipids (IMCL), hepatocellular lipids (HCL) and the amount of subcutaneous (SAT) and visceral adipose tissue (VAT) in 16 pairs of healthy monozygotic twins (MZ) discordant for BMI. A second independent cohort of 12 healthy volunteers was used to measure DSAT unsaturation and IMCL with standardized measurement time. One volunteer also underwent repeated random measurements of DSAT unsaturation and IMCL. ResultsIn accordance with biopsy studies SSAT unsaturation was higher in the heavier twins (15.2±1.0% vs. 14.4±1.5%, P=0.024) and associated with SAT volume (R=0.672, P=0.001). DSAT unsaturation did not differ between twins (11.4±0.8 vs. 11.0±1.0, P=0.267) and associated inversely with IMCL content (R=−0.462, P=0.001). The inverse association between DSAT unsaturation and IMCL was also present in the participants of the second cohort (R=−0.641, P=0.025) and for the repeated sampling at random of one person (R=−0.765, P=0.027). ConclusionsDSAT and SSAT FA unsaturation shows distinct associations with obesity and IMCL in MZ twins, reflecting compartment-specific metabolic activities. The FA unsaturation in the DSAT depot associates inversely with IMCL content, which raises the possibility of cross talk between the DSAT depot and the rapid turnover IMCL depot.

Decoration of intramyocellular lipid droplets with PLIN5 modulates fasting-induced insulin resistance and lipotoxicity in humans

Aims/hypothesisIn contrast to insulin-resistant individuals, insulin-sensitive athletes possess high intramyocellular lipid content (IMCL), good mitochondrial function and high perilipin 5 (PLIN5) levels, suggesting a role for PLIN5 in benign IMCL storage. We hypothesised a role for PLIN5 in modulating fasting-mediated insulin resistance.MethodsTwelve men were fasted for 60 h, before and after which muscle biopsies were taken and stained for lipid droplets (LDs), PLIN5 and laminin. Confocal microscopy images were analysed for LD size, number, PLIN5 association and subcellular distribution.ResultsFasting elevated IMCL content 2.8-fold and reduced insulin sensitivity (by 55%). Individuals with the most prominent increase in IMCL showed the least reduction in insulin sensitivity (r = 0.657; p = 0.028) and mitochondrial function (r = 0.896; p = 0.006). During fasting, PLIN5 gene expression or PLIN5 protein content in muscle homogenates was unaffected, microscopy analyses revealed that the fraction of PLIN5 associated with LDs (PLIN5+) increased significantly (+26%) upon fasting, suggesting PLIN5 redistribution. The significant increase in LD number (+23%) and size (+23%) upon fasting was entirely accounted for by PLIN5+ LDs, not by LDs devoid of PLIN5. Also the association between IMCL storage capacity and insulin resistance and mitochondrial dysfunction was only apparent for PLIN5+ LDs.Conclusions/interpretationFasting results in subcellular redistribution of PLIN5 and promotes the capacity to store excess fat in larger and more numerous PLIN5-decorated LDs. This associates with blunting of fasting-induced insulin resistance and mitochondrial dysfunction, suggesting a role for PLIN5 in the modulation of fasting-mediated lipotoxicity.Trial registration:trialregister.nl NTR 2042Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-016-3865-z) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Relative Contribution of Intramyocellular Lipid to Whole-Body Fat Oxidation Is Reduced With Age but Subsarcolemmal Lipid Accumulation and Insulin Resistance Are Only Associated With Overweight Individuals.

Insulin resistance is closely related to intramyocellular lipid (IMCL) accumulation, and both are associated with increasing age. It remains to be determined to what extent perturbations in IMCL metabolism are related to the aging process per se. On two separate occasions, whole-body and muscle insulin sensitivity (euglycemic-hyperinsulinemic clamp with 2-deoxyglucose) and fat utilization during 1 h of exercise at 50% VO2max ([U-(13)C]palmitate infusion combined with electron microscopy of IMCL) were determined in young lean (YL), old lean (OL), and old overweight (OO) males. OL displayed IMCL content and insulin sensitivity comparable with those in YL, whereas OO were markedly insulin resistant and had more than twofold greater IMCL in the subsarcolemmal (SSL) region. Indeed, whereas the plasma free fatty acid Ra and Rd were twice those of YL in both OL and OO, SSL area only increased during exercise in OO. Thus, skeletal muscle insulin resistance and lipid accumulation often observed in older individuals are likely due to lifestyle factors rather than inherent aging of skeletal muscle as usually reported. However, age per se appears to cause exacerbated adipose tissue lipolysis, suggesting that strategies to reduce muscle lipid delivery and improve adipose tissue function may be warranted in older overweight individuals.

Intramyocellular lipid content in subjects with impaired fasting glucose after telmisartan treatment, a randomised cross-over trial

Ectopic lipid accumulation in skeletal muscle is associated with insulin resistance. Telmisartan improves metabolic parameters in type 2 diabetic patients. The aim of our study was to evaluate the in vivo effect of telmisartan on intramyocellular lipid content (IMCL) in subjects with impaired fasting glucose (IFG) by magnetic resonance spectroscopy (MRS). We enrolled 10 subjects with IFG in a cross-over, placebo-controlled, randomized, double-blind trial, treated with 3 weeks of telmisartan (160 mg daily) or placebo. After completing each treatment, a hyperinsulinaemic euglycaemic clamp (1 mU/kg per min; 5 mmol/l; 120 min) to assess insulin action (metabolic clearance rate of glucose, MCR) and 1H MRS of the m. tibialis anterior using a MR Scanner Siemens Vision operating at 1.5 T to evaluate IMCL content, were performed. Plasma adipokine levels were determined simultaneously. Telmisartan treatment resulted in a lower fasting plasma glucose (FPG) (p < 0.05), but insulin action was comparable to after placebo. Telmisartan did not affect IMCL content. After placebo, IMCL correlated negatively with total cholesterol (p < 0.001), MCR (p < 0.05) and adiponectin (p < 0.05) and positively with FPG (p < 0.05). After telmisartan treatment there was only a positive correlation between IMCL and TNFα (p < 0.05). IMCL content is related to parameters of glucose metabolism and insulin action in sedentary IFG subjects. A short telmisartan treatment did not affect the IMCL content despite its positive effect on FPG. The improvement in FPG was probably mediated through interference with other metabolic pathways.

Effects of acute exercise on lipid content and dietary lipid uptake in liver and skeletal muscle of lean and diabetic rats.

Insulin resistance is associated with ectopic lipid accumulation. Physical activity improves insulin sensitivity, but the impact of exercise on lipid handling in insulin-resistant tissues remains to be elucidated. The present study characterizes the effects of acute exercise on lipid content and dietary lipid partitioning in liver and skeletal muscle of lean and diabetic rats by use of magnetic resonance spectroscopy (MRS). After baseline measurements, rats were randomized to exercise or no-exercise groups. A subset of animals was subjected to MRS directly after 1 h of treadmill running for measurement of total intrahepatocellular lipid (IHCL) and intramyocellular lipid (IMCL) content (n=7 lean and diabetic rats). The other animals were administered 13C-labeled lipids orally after treadmill visit (with or without exercise) followed by MRS measurements after 4 and 24 h to determine the 13C enrichment of IHCL and IMCL (n=8 per group). Total IHCL and IMCL content were fivefold higher in diabetic vs. lean rats (P<0.001). Exercise did not significantly affect IHCL content but reduced IMCL by 25±7 and 33±4% in lean and diabetic rats (P<0.05), respectively. Uptake of dietary lipids in liver and muscle was 2.3-fold greater in diabetic vs. lean rats (P<0.05). Prior exercise did not significantly modulate dietary lipid uptake into muscle, but in liver of both lean and diabetic rats, lipid uptake was 44% reduced after acute exercise (P<0.05). In conclusion, IMCL but not IHCL represents a viable substrate source during exercise in both lean and diabetic rats, and exercise differentially affects dietary lipid uptake in muscle and liver.

A 3-day high-fat/low-carbohydrate diet does not alter exercise-induced growth hormone response in healthy males

ObjectiveThe purpose of the present study was to examine the effects of 3days isoenergetic high-fat/low-carbohydrate diet (HF-LC) relative to low-fat/high-carbohydrate diet (LF-HC) on the exercise-induced growth hormone (GH) response in healthy male subjects. DesignTen healthy young males participated in this study. Each subject consumed the HF-LC (18±1% protein, 61±2% fat, 21±1% carbohydrate, 2720kcal per day) for 3 consecutive days after consuming the LF-HC (18±1% protein, 20±1% fat, 62±1% carbohydrate, 2755kcal per day) for 3 consecutive days. After each dietary intervention period, the hormonal and metabolic responses to an acute exercise (30min of continuous pedaling at 60% of V˙O2max) were compared. The intramyocellular lipid (IMCL) contents in the vastus lateralis, soleus, and tibialis anterior were evaluated by proton magnetic resonance spectroscopy. ResultsSerum GH concentrations increased significantly during the exercise after both the HF-LC and LF-HC periods (P<0.05). However, the exercise-induced GH response was not significantly different between the two periods. Fat utilization and lipolytic responses during the exercise were enhanced significantly after the HF-LC period compared with the LF-HC period. IMCL content did not differ significantly in any portion of muscle after the dietary interventions. ConclusionsWe could not show that short-term HF-LC consumption changed significantly exercise-induced GH response or IMCL content in healthy young males.

Are hepatic and soleus lipid content, assessed by magnetic resonance spectroscopy, associated with low birth weight or insulin resistance in a rural Indian population of healthy young men?

To assess young healthy men from rural India, who had normal or low birth weights, using magnetic resonance spectroscopy to determine the potential differences in ectopic fat storage between birth weight groups, and to determine if ectopic fat storage was associated with insulin resistance in this population. A total of 54 lean men with normal birth weight and 49 lean men with low birth weight (age range 18-22 years) from rural India were recruited. All the men underwent anthropometry, magnetic resonance spectroscopy, a hyperinsulinaemic-euglycaemic clamp and a dual-energy X-ray absorptiometry. The median (interquartile range) values for hepatic cellular lipids, intramyocellular lipids and extramyocellular lipids, measured using magnetic resonance spectroscopy were 0.76 (0.1-1.8)%, 1.27 (1.0-2.3)% and 1.89 (1.3-3.2)%, respectively, for the normal birth weight group and 0.4 (0.1-1.3)%, 1.38 (0.9-2.2)% and 2.07 (1.2-2.8)%, respectively, for the low birth weight group (P > 0.05). No difference in ectopic fat storage was observed between the low and normal birth weight groups, with or without adjustment for age and total fat percentage. Homeostatic model assessment of insulin resistance values were not associated with hepatic cellular, intramyocellular or extramyocellular lipid content in any of the groups. Total fat percentage was the only independent predictor of intramyocellular and extramyocellular lipid content. Young and lean men from rural India with low birth weight were not observed to have ectopic fat storage in the liver or muscle, and the amount of liver and muscle fat was unrelated to insulin resistance. Older age and/or an urban affluent lifestyle may be required to show a potential role of ectopic fat storage on insulin resistance in Indian people with low or normal birth weight.

Reduced CD300LG mRNA tissue expression, increased intramyocellular lipid content and impaired glucose metabolism in healthy male carriers of Arg82Cys in CD300LG: a novel genometabolic cross-link between CD300LG and common metabolic phenotypes

BackgroundCD300LG rs72836561 (c.313C>T, p.Arg82Cys) has in genetic-epidemiological studies been associated with the lipoprotein abnormalities of the metabolic syndrome. CD300LG belongs to the CD300-family of membrane-bound molecules which have the ability...

In vivo MRS of Muscle, Liver, Heart and Other Organs: A Review of Techniques and Applications

As MRI has been used in biomedical research and medicine since the 1970s, Magnetic Resonance Spectroscopy (MRS) has been employed to study biochemical alterations in living animals and humans. By taking advantage of its noninvasive nature, 1H, 13C and 31P MRS are being actively utilized in clinical and biomedical studies to detect lipids, metabolites, and/or kinetic information, such as acetyl carnitine content and ATP synthesis rates in vivo. These data would be quite difficult to assess by other modalities. Furthermore, many studies have indicated that in vivo values obtained by MRS show a close correlation with important metabolic parameters (e.g., hepatic and intramyocellular lipid content by 1H-MRS correlated with insulin sensitivity), which adds value of MRS. Moreover, hepatic glycogen synthesis and breakdown can be directly detected by 13C-MRS, whereas in vivo ATP synthesis rates in mitochondria can be assessed by 31P-MRS as well. These in vivo data offer critical metabolic information in animals and humans, and often serve as useful biomarkers for the pathophysiology and state of a disease. Thus, in this review, important and frequently used modalities and applications of MRS in muscle, liver, and other organs are described.

Fat Infiltration in the Leg is Associated with Bone Geometry and Physical Function in Healthy Older Women.

The objective of this study was to estimate the associations between muscular fat infiltration, tibia bone mineral quantity and distribution, and physical function in healthy older women. Thirty-five women (aged 60-75 years, mean 70 years) were recruited from the community. Percent intramuscular fat (%IntraMF) within the right leg tibialis anterior, soleus, and gastrocnemius muscles and total intermuscular fat (IMF) were segmented from magnetic resonance imaging scans at the mid-calf. Intramyocellular lipid (IMCL) content in the right tibialis anterior was measured with proton magnetic resonance spectroscopy. Right tibia bone content, area, and strength were measured at the 4, 14, and 66% sites using peripheral quantitative computed tomography. Physical function was assessed by gait speed on the 20 m walking test. After adjusting for age, body size, and activity level, %IntraMF had a negative association with bone content and area at all tibia sites (r = -0.31 to -0.03). Conversely, greater IMF was associated with increased bone content and area (r = 0.04-0.32). Correlation coefficients for the association between IMCL and bone were negative (r = -0.44 to -0.03). All measures of fat infiltration had a negative association with observed physical function (r = -0.42 to -0.04). Our findings suggest that muscular fat infiltration in the leg of healthy postmenopausal women has a compartment-specific relationship with bone status and physical function. Minimizing fat accumulation within and between muscle compartments may prevent bone fragility and functional decline in women.

Intramyocellular and Extramyocellular Lipids Are Associated With Arterial Stiffness.

Obese and overweight patients are at increased risk of arterial stiffness, and visceral, epicardial and hepatic fat accumulation is associated with cardiovascular disease risk. In general, muscular lipids are stored either in interstitial adipose tissue (extramyocellular lipid (EMCL)) or in lipid droplets within muscle cells (intramyocellular lipid (IMCL)). However, the association between IMCL or EMCL content and arterial stiffness remains unclear. This cross-sectional study aimed to clarify this association. A total of 237 subjects (18-81 years) were enrolled in this study. The IMCL and EMCL contents of the right vastus lateralis muscle were evaluated by proton magnetic resonance spectroscopy. Arterial stiffness was estimated using brachial-ankle pulse wave velocity (baPWV). There were significant correlations between baPWV and the contents of both IMCL (R = -0.23, P < 0.001) and EMCL (R = 0.53, P < 0.001) in all subjects. The baPWV negatively correlated with IMCL content (R = -0.45, P < 0.001) in females only. In contrast, significant positive correlations were observed between baPWV and EMCL content in both males (R = 0.59, P < 0.001) and females (R = 0.55, P < 0.001). IMCL and EMCL contents contributed independently to baPWV variation after adjustment for age, sex, body mass index, visceral and subcutaneous abdominal fat, upper and lower limb fat, blood pressure, heart rate, and lipid profiles. These results suggest that IMCL and EMCL contents may be a risk factor for arterial stiffness, and this association differed with gender and age.

The single nucleotide polymorphism Gly482Ser in the PGC-1α gene impairs exercise-induced slow-twitch muscle fibre transformation in humans.

PGC-1α (peroxisome proliferator-activated receptor γ co-activator 1α) is an important regulator of mitochondrial biogenesis and a master regulator of enzymes involved in oxidative phosphorylation. Recent evidence demonstrated that the Gly482Ser single nucleotide polymorphism (SNP) in the PGC-1α gene affects insulin sensitivity, blood lipid metabolism and binding to myocyte enhancer factor 2 (MEF2). Individuals carrying this SNP were shown to have a reduced cardiorespiratory fitness and a higher risk to develop type 2 diabetes. Here, we investigated the responses of untrained men with the Gly482Ser SNP to a 10 week programme of endurance training (cycling, 3 x 60 min/week, heart rate at 70-90% VO2peak). Quantitative data from analysis of biopsies from vastus lateralis muscle revealed that the SNP group, in contrast to the control group, lacked a training-induced increase in content of slow contracting oxidative fibres. Capillary supply, mitochondrial density, mitochondrial enzyme activities and intramyocellular lipid content increased similarly in both groups. These results indicate that the impaired binding of MEF2 to PGC-1α in humans with this SNP impedes exercise-induced fast-to-slow muscle fibre transformation.

High vs. Low Responders to Exercise: Role of Epigenetic Modifications in Altering PGC1α Gene Expression and Intramyocellular Lipid Content in Skeletal Muscle

Interindividual responses to exercise training exist in PGC1α gene expression and may be due to plasticity of epigenetic modifications. Here, we determined if exercise‐induced variation in PGC1α DNA methylation was associated with interindividual responses in ‐1N position, gene expression and intramyocellular lipid (IMCL) content. Sedentary, lean men (n=15, aged 24±1 yrs, BMI 23.8±0.4) underwent an acute bout of exercise (50% VO2max, ~650 kcal). Muscle biopsies were taken before and immediately after exercise. PGC1α DNA methylation of the regulatory ‐260 nucleotide (nt) and ‐1N position were determined in duplicate via pyrosequencing and scanning PCR, respectively. PGC1α expression was measured by qRT‐PCR and IMCL via BODIPY staining. Subjects were divided into high (change in DNA methylation percentage 蠄 0; N=7) or low (change in DNA methylation percentage &gt; 0; N=8) responders. High but not low responders exhibited repositioning of the ‐1N away from the ‐260nt, showed a significant increase in PGC1α expression (P = 0.03) and tended to have decreased IMCL content (P = 0.17). Exercise–induced DNA hypomethylation at the PGC1α ‐260nt and repositioning of the ‐1N upstream of the regulatory ‐260nt are linked to increased gene expression and possibly decreased IMCL content. Epigenetic regulation of PGC1α may contribute to interindividual responsiveness to exercise training.

Lipid‐Induced Anabolic Resistance in Skeletal Muscle is Associated with Inflammation in Aging, but Not Obesity

The loss of skeletal muscle mass is observed in many pathophysiological conditions including, aging and obesity. Chronic inflammation is observed with aging and obesity may play a critical role in the muscle's resistance to anabolic stimulation. A characteristic metabolic feature of both these conditions is an increase in the accumulation of intramyocellular lipid (IMCL) content. Therefore, we tested the hypothesis that lipid-induced anabolic resistance is mediated by inflammation in both aging and obesity. In order to test this hypothesis we used C57BL/6 mice aged 6 months and fed a control diet (YNG, 15% fat/kcal) or a high-fat (FAT, 60% fat/kcal) and mice aged 24 months fed a control diet (OLD) for 12 wk. The accumulation of intramuscular lipids was increased in both OLD and FAT compared to YNG. The phosphorylation of anabolic signaling components was increased in all groups after insulin stimulation but differentially affected in OLD and FAT. Differences in the activation and gene expression of the NFκB proinflammatory signaling pathway were only observed in OLD, but not FAT. We conclude that the accumulation of lipids during aging and obesity have divergent effects on inflammation in skeletal muscle.