Statin withdrawal and health-related quality of life in a primary cardiovascular prevention cohort.

PURPOSE: While some work has been done on Health-Related Quality of Life (HRQoL) in statin users, none has focused specifically on statin-associated muscle symptoms (SAMS) sufferers. The objective was to assess self-reported HRQoL, before and after statin withdrawal, in patients reporting SAMS. We hypothesized that the presence of SAMS associated with decreased self-reported physical and mental well-being. METHODS: Patients (50 men/28 women [M/W], aged 49 ± 9 years [Mean ± SD]) in primary cardiovascular prevention were recruited into three cohorts: statin users with (SAMS, 29 M/18W) or without symptoms (No SAMS, 10 M/5W) and controls (11 M/5W). The Short Form 36 Health Survey (SF-36) was used to assess HRQoL. All variables were measured before and after 2 months of statin withdrawal, and repeated measures analyses were used to verify withdrawal and group effects as well as their interaction. RESULTS: SF-36 physical and mental component scores (respectively, PCS and MCS) were lower in the SAMS group compared with other groups (both p < 0.01). Statin withdrawal led to an increase in LDL cholesterol for statin users (+69.0%, p < 0.01) and an improvement in well-being in the SAMS group, other groups showing no change. A time x category interaction (p = 0.02) was seen for PCS and post hoc analyses showed that statin withdrawal improved PCS and MCS (respectively, +12.5% [ES 0.77] and +5.1% [ES 0.27], both p < 0.05) in the SAMS group. CONCLUSION: Patients self-reporting SAMS showed improved HRQoL following drug withdrawal, but this was mirrored by a rise in LDL cholesterol. These findings should be considered by clinicians in the evaluation and follow-up of treatment with statins.

Gene expression in a rarely studied intraabdominal adipose depot, the round ligament, in severely obese women: A pilot study.

Gene expression (qPCR) was compared in round ligament (RL), omental (OME) and mesenteric (MES) ATs from 48 severely obese women (BMI, 54±11 kg/m(2); 38±9 yrs). The mRNA levels of enzymes of lipid metabolism (LPL, HSL, and PDE-3B), cortisol production (11ßHSD-1), adipogenesis (PPAR-γ1/2), thrombosis and inflammation (PAI-1, IL-6, TNF-α and adiponectin) were determined. AT-LPL mRNA was highest in RL. The highest PDE-3B and lowest PAI-1 mRNA levels were observed in RL and MES. The lowest IL-6 and TNF-α and the highest adiponectin and PPAR-g1/2 mRNA levels were found in RL AT. 11ßHSD-1 was highest in RL and OME. A higher lipogenic and adipogenic, and lower pro-inflammatory and pro-thrombotic profiles of the RL suggest a lesser deleterious impact on obesity-related complications.

Gene expression of different adipose tissues of severely obese women with or without a dysmetabolic profile.

Despite well-established variations in the health risks posed by visceral vs. subcutaneous abdominal (SCABD) fat depots, surprisingly little is known on the differences within a given adipose tissue (AT) among severely obese patients displaying varying metabolic dysfunction. We thus compared, by quantitative PCR, the expression profile of a number of genes in the SCABD, omental (OME), and mesenteric (MES) depots of severely obese women with (DYS; n = 25) or without (NDYS; n = 23) a dysmetabolic profile. Fasting insulinemia and HOmeostasis Model Assessment-insulin resistance (HOMA-IR) were higher and plasma adiponectin level lower in DYS women (p < 0.05). Among enzymes involved in fatty acid metabolism and local cortisol production, phosphodiesterase-3B expression was lower in SCABD and MES fat, while 11ß-hydroxysteroid dehydrogenase type 1 mRNA levels were higher in visceral depots of DYS women (p < 0.05). Regarding vascular homeostasis and inflammation, plasminogen activator inhibitor-1 and interleukin-6 mRNA levels were higher in OME fat, while adiponectin expression was lower in SCABD and OME ATs of DYS women (p < 0.05). Finally, HOMA-IR was positively associated with SCABD AT IL6 mRNA, only in DYS women (r = 0.47; p < 0.05). In conclusion, although metabolic and secretory characteristics of all depots vary with subjects' metabolic profile, we find little evidence for a protective role of SCABD AT and no evidence for a further deleterious role of MES fat in DYS vs. NDYS severely obese women. Regional variation in the overall gene expression revealed that OME and MES fat were more closely related to each other in DYS women, while SCABD and MES depots showed greater resemblance in NDYS women.

Anthropometric characteristics account for time to exhaustion in cycling.

This study examined the relationship between the phenotypic and anthropometric characteristics and the cycling time to exhaustion (Tlim) at the maximal aerobic power output (Pmax). 12 (7 men, 5 women) physically-active participants performed a square-wave test at Pmax to determine the maximal time limit. Muscle histochemistry, enzymatic activities and buffer capacity were determined from a vastus lateralis muscle biopsy, lean body mass (LBM) by hydrostatic weighing, and total (TV) and lean (LV) volumes of the thigh by anthropometric measurements. The mean (±SD) Tlim was 235±84 s (score range: 108-425 s). No relationship was found between Tlim and any muscle phenotypes. However, we observed a strong, linear relationship between Tlim and LBM (r=0.84, P<0.05). Thigh TV and LV displayed weaker correlation coefficients with Tlim (r=0.66 and r=0.73, respectively; P<0.05). We further estimated the femur length and found this measure to correlate with Tlim (r=0.81, P<0.05). This study suggests that muscle phenotypes may not be representative of Tlim. Rather, anthropometric characteristics account for such performance by conferring a biomechanical advantage in cycling. We conclude that, in addition to metabolic factors, anthropometric characteristics with reasonable accuracy predict Tlim in cycling, and may account for the large inter-subject variability observed in previous studies.

Validation of a simple index (SIisOGTT) of insulin sensitivity in a population of sedentary men.

AIM: The ongoing obesity epidemic is associated with numerous health problems related to altered metabolic function. Among these is type 2 diabetes, characterized by lowered insulin sensitivity (IS). Consequently, the development of simple indices to assess IS has research and clinical importance. The SI(is)OGTT, a new index of IS, was recently described by Bastard et al. (Diabetes & Metabolism 2007;33:261-8), and validated in sedentary, non-diabetic, overweight and obese postmenopausal women. The aim of the present study was to validate the index in men. METHODS: The data used in this project came from sedentary men (n=36), aged 34-53 years, all of whom underwent a hyperinsulinaemic-euglycaemic clamp and 2-hour oral glucose tolerance test (OGTT). Correlations with M/I (glucose infusion rate [GIR] divided by insulin concentration), GIR and GIR divided by fat-free mass (FFM) were obtained by four well-known indices (HOMA, QUICKI, Cederholm and Matsuda) as well as with the new SI(is)OGTT index. Pearson correlations and Bland-Altman analyses were obtained for every index versus clamp value. RESULTS: The best correlate of IS in the present study was the SI(is)OGTT (r=0.84, P<0.0001). The agreement of this method with the hyperinsulinaemic-euglycaemic clamp, as assessed by Bland-Altman plots, was similar to those of the other indices and to those previously described in postmenopausal women. CONCLUSION: The new index proposed by Bastard et al. is as good a predictor of IS in sedentary men as the other commonly used indices, and appears to be as reliable in this population as it was in the original study of postmenopausal women.

Muscle adiposity and body fat distribution in type 1 and type 2 diabetes: varying relationships according to diabetes type.

OBJECTIVE: To compare the relationships between markers of total and regional adiposity with muscle fat infiltration in type 1 diabetic and type 2 diabetic subjects and their respective nondiabetic controls, and to document these relationships in type 1 diabetic subjects. DESIGN: Cross-sectional study. SUBJECTS: In total, 86 healthy, with type 1 diabetes, type 2 diabetes or control subjects. Each diabetic group was matched for age, sex and body mass index with its respective nondiabetic control group. MEASUREMENTS: Measures of body composition (hydrodensitometry), fat distribution (waist circumference, abdominal and mid-thigh computed tomography scans) and blood lipid profiles were assessed. RESULTS: Low attenuation mid-thigh muscle surface correlated similarly with markers of adiposity and body composition in all groups, regardless of diabetes status, except for visceral adipose tissue and waist circumference. Indeed, relationships between visceral adiposity and muscle adiposity were significantly stronger in type 2 vs type 1 diabetic subjects (P<0.05 for comparison of slopes). In addition, in well-controlled type 1 diabetic subjects (mean HbA(1c) of 6.8%), daily insulin requirements tended to correlate with low attenuation mid-thigh muscle surface, a specific component of fat-rich muscle (r=0.36, P=0.08), but not with glycemic control (HbA(1c)). CONCLUSION: This study suggests that the relationship of central adiposity and muscle adiposity is modulated by diabetes status and is stronger in the insulin resistant diabetes type (type 2 diabetes). In well-controlled nonobese type 1 diabetic subjects, the relationship between muscle fat accumulation and insulin sensitivity was also maintained.

Adaptation of the diaphragm and the vastus lateralis in mild-to-moderate COPD.

The chronology of diaphragm and vastus lateralis adaptation in chronic obstructive pulmonary disease (COPD) has not been studied. The hypothesis of this study was that muscle changes would occur earlier in the diaphragm than in the vastus lateralis in COPD, a finding that would suggest that local factors would be more important than systemic factors in determining the muscle phenotypic expression, at least in mild-to-moderate disease. The adaptation of the vastus lateralis and diaphragm muscles was evaluated in patients with mild-to-moderate COPD and in subjects with normal pulmonary function. In both groups, the oxidative potential and the number of lipofuscin inclusions were higher in the diaphragm than in the vastus lateralis. Compared to control, the diaphragm in COPD had a higher oxidative capacity and a higher proportion of type I fibres, with a reciprocal decrease in type IIA fibres, while there was no difference in diaphragmatic cross sectional areas, capillarisation and lipofuscin inclusions. No significant differences were found in the vastus lateralis from both groups. In conclusion, these data indicate that the diaphragm in controls and in chronic obstructive pulmonary disease has a higher oxidative potential than the vastus lateralis, and that muscle adaptation occurs earlier in the diaphragm than in the vastus lateralis in mild-to-moderate chronic obstructive pulmonary disease.

Associations between cardiorespiratory responses to exercise and the C34T AMPD1 gene polymorphism in the HERITAGE Family Study.

The associations of the C34T polymorphism of the adenosine monophosphate deaminase 1 (AMPD1) gene with cardiorespiratory phenotypes were tested during cycling exercise at absolute and relative power outputs progressing to exhaustion before and after endurance training for 20 wk in the HERITAGE Family Study cohort (n = 779). Since no blacks were mutant homozygotes (TT), only whites were considered for analysis (400 normal homozygotes, CC; 97 heterozygotes, CT; and 6 TT). For sedentary state, cycling at the absolute power output of 50 W resulted in a higher rating of perceived exertion in TT (P < 0.0001). At the relative intensity of 60% of Vo(2 max), stroke volume was lower in TT (P < 0.05). Maximal values for power output, systolic blood pressure, heart rate, Vco(2), and respiratory exchange ratio were lower in TT (P < 0.05). The cardiorespiratory training response at 50 W and at 60% of Vo(2 max) was similar across C34T-AMPD1 genotypes. However, the maximal values for ventilation, Vo(2), and Vco(2) during exercise increased less in TT (P < 0.01). The results indicate that subjects with the TT genotype at the C34T AMPD1 gene have diminished exercise capacity and cardiorespiratory responses to exercise in the sedentary state. Furthermore, the training response of ventilatory phenotypes during maximal exercise is more limited in TT.

Relation between in vivo and in vitro measurements of skeletal muscle oxidative metabolism.

The relationships between in vivo (31)P magnetic resonance spectroscopy (MRS) and in vitro markers of oxidative capacity (mitochondrial function) were determined in 27 women with varying levels of physical fitness. Following 90-s isometric plantar flexion exercises, calf muscle mitochondrial function was determined from the phosphocreatine (PCr) recovery time constant, the adenosine diphosphate (ADP) recovery time constant, the rate of change of PCr during the initial 14 s of recovery, and the apparent maximum rate of oxidative adenosine triphosphate (ATP) synthesis (Q(max)). Muscle fiber type distribution (I, IIa, IIx), citrate synthase (CS) activity, and cytochrome c oxidase (COX) activity were determined from a biopsy sample of lateral gastrocnemius. MRS markers of mitochondrial function correlated moderately (P < 0.05) with the percentage of type IIa oxidative fibers (r = 0.41 to 0.66) and CS activity (r = 0.48 to 0.64), but only weakly with COX activity (r = 0.03 to 0.26, P > 0.05). These results support the use of MRS to determine mitochondrial function in vivo.

Fat content in individual muscle fibers of lean and obese subjects.

OBJECTIVE: To examine skeletal muscle intracellular triglyceride concentration in different fiber types in relation to obesity. DESIGN: Skeletal muscle fiber type distribution and intracellular lipid content were measured in vastus lateralis samples obtained by needle biopsy from lean and obese individuals. SUBJECTS: Seven lean controls (body mass index (BMI) 23.0+/-3.3 kg/m(2); mean+/-s.d.) and 14 obese (BMI 33.7+/-2.7 kg/m(2)) individuals; both groups included comparable proportions of men and women. MEASUREMENTS: Samples were histochemically stained for the identification of muscle fiber types (myosin ATPase) and intracellular lipid aggregates (oil red O dye). The number and size of fat aggregates as well as their concentration within type I, IIA and IIB muscle fiber types were measured. The cellular distribution of the lipid aggregates was also examined. RESULTS: The size of fat aggregates was not affected by obesity but the number of lipid droplets within muscle fibers was twice as abundant in obese compared to lean individuals. This was seen in type I (298+/-135 vs 129+/-75; obese vs lean, P<0.05), IIA (132+/-67 vs 79+/-29; P<0.05), and IIB (103+/-63 vs 51+/-13; P<0.05) muscle fibers. A more central distribution of lipid droplets was observed in muscle fibers of obese compared to lean subjects (27.2+/-5.7 vs 19.7+/-6.4%; P<0.05). CONCLUSION: The higher number of lipid aggregates and the disposition to a greater central distribution in all fiber types in obesity indicate important changes in lipid metabolism and/or storage that are fiber type-independent.

Elevated intramyocellular lipid concentration in obese subjects is not reduced after diet and exercise training.

To determine the effects of weight loss on intramyocellular energy substrates, vastus lateralis muscle biopsies were taken from six obese subjects (body mass index 34 +/- 5 kg/m(2)) before, after 15 wk of energy restriction (ER; -700 kcal/day), and after a further average 20.7 +/- 1.6 wk of endurance training plus low-fat diet (ET-LFD). Body weight fell from 100 +/- 6 to 89 +/- 6 kg during ER and to 84 +/- 4 kg after ET-LFD. Lipids and glycogen were histochemically measured in type I, IIA, and IIB fibers. Total muscle glycogen content (MGC; per 100 fibers) decreased after ER [from 72 +/- 13 to 55 +/- 8 arbitrary units (AU)]. A similar but not significant decrease was seen in total muscle lipid content (MLC; 14 +/- 5 to 9 +/- 1 AU). After ET-LFD, MGC returned to initial values (74 +/- 8 AU), and MLC approached near-initial values (12 +/- 3 AU). Individual fiber lipid concentration did not change throughout the protocol in all fiber types, whereas glycogen concentration increased after ET-LFD. The training effects of ET-LFD were measured as increasing activities of key mitochondrial enzymes. Although total muscle energy reserves can be reduced after weight loss, their concentration within individual myofibers remains elevated. Weight loss does not appear sufficient to correct the potential detrimental effects of high intracellular lipid concentrations.

The stimulation-induced increase in skeletal muscle glycogen synthase content is impaired in carriers of the glycogen synthase XbaI gene polymorphism.

Associations between glycogen synthase gene (GYS1) polymorphism and states of insulin resistance and type 2 diabetes have been reported. The purpose of this study was to establish if the GYS1 genotype impacts on the content of glycogen synthase (GS) protein in muscle measured under basal and stimulated conditions. To examine this, GYS1 XbaI and Met416Val polymorphisms and thigh muscle GYS1 protein content were determined at rest, both before and after several weeks of neuromuscular electrical stimulation in carriers and noncarriers of the mutations. The allelic frequency was 0.086 for the XbaI mutation (A2) and 0.006 for the Met416Val in our cohort of French-Canadian subjects. When measured at rest, the GS protein content in muscle was similar among carriers and noncarriers of the XbaI variant. However, the stimulation-induced increase (23%) in the amount of GS muscle protein normally seen in wildtype individuals was impaired in those carrying the XbaI mutation. These data demonstrate that some individuals, because of their genetic background, are unable to stimulate the process of GS protein accumulation in skeletal muscle. These results could explain why some individuals appear to be genetically predisposed to developing skeletal muscle insulin resistance when exposed to unfavorable metabolic environments.

Cloning and developmental expression of a nuclear ubiquitin-conjugating enzyme (DmUbc9) that interacts with small heat shock proteins in Drosophila melanogaster.

In a two hybrid screen designed to identify proteins that interact with small heat shock proteins (sHsps), a Drosophila melanogaster homologue of yeast and human ubc9 (Dmubc9) was found to interact with Drosophila Hsp23. Further, two-hybrid system analysis reveals DmUbc9 interaction with Drosophila and mammalian Hsp27. In situ hybridization localizes Dmubc9 as a doublet at locus 21D on chromosome 2L, and genomic cloning of the gene reveals a single open reading frame without introns. The predicted Dmubc9 protein sequence shares a very high level of homology with mouse (85.4%) and human (> or = 82.9%) Ubc9. Genetic complementation analysis show that Dmubc9 functionally rescues a temperature-sensitive S. cerevisiae ubc9ts mutant. Co-immunoprecipitation with antibody raised against DmUbc9 confirms the interaction with Drosophila Hsp23 and Hsp26 and preferentially with Hsp27. The DmUbc9 protein, which localizes primarily to the nucleus in Drosophila S2 cells, is found at high levels in embryos but is also present at lower levels throughout development. The significance of the sHsp-Ubc9 interaction is discussed.

Oxidative damage and antioxidants in Rana sylvatica, the freeze-tolerant wood frog.

Freeze-tolerant wood frogs (Rana sylvatica) must endure prolonged ischemia on freezing. Reperfusion on thawing brings with it the potential or oxidative damage due to reactive oxygen species formation, a well-known consequence of mammalian ischemia-reperfusion. To determine whether oxidative damage occurs during thawing and how frogs deal with this, we examined oxidative damage and antioxidant and prooxidant systems in tissues of Rana sylvatica and a nonfreezing relative, Rana pipiens. Glutathione status indicated little oxidative stress in tissues during freezing or thawing; an increase of the glutathione pool in the oxidized form was observed during freezing only in Rana sylvatica kidney (by 85%) and brain (by 33%). Oxidative damage to tissue lipids, measured as the levels of thiobarbituric acid-reactive substances and/or by an Fe(III)-xylenol orange assay, did not increase above control values pver a freeze-thaw time course. Correlative data showing increased activities of some antioxidant enzymes during freezing, notably glutathione peroxidase (increasing 1.2- to 2.5-fold), as well as constitutively higher activities of antioxidant enzymes and higher levels of glutathione in the freeze-tolerant species compared with Rana pipiens, suggest that antioxidant defenses play a key role in amphibian freeze tolerance.