Search PubMed⌕ Search

Biomedical subjects

Robert E Ferrell

Publications and source records attributed to Robert E Ferrell.

At least 37 records · Page 2Linked to original sources

Estimates of African, European and Native American ancestry in Afro-Caribbean men on the island of Tobago.

BACKGROUND/AIMS: The Tobago Afro-Caribbean population is a valuable resource for studying the genetics of diseases that show significant differences in prevalence between populations of African descent and populations of other ancestries. Empirical confirmation of low European and Native American admixture may help in clarifying the ethnic variation in risk for such diseases. We hypothesize that the degree of European and Native American admixture in the Tobago population is low. METHODS: Admixture was estimated in a random sample of 220 men, from a population-based prostate cancer screening survey of 3,082 Tobago males, aged 40 to 79 years. We used a set of six autosomal markers with large allele frequency differences between the major ethnic populations involved in the admixture process, Europeans, Native Americans and West Africans. RESULTS: The ancestral proportions of Tobago population are estimated as 94.0+/-1.2% African, 4.6+/-3.4% European and 1.4+/-3.6% Native American. CONCLUSIONS: We conclude that Tobago Afro-Caribbean men are predominantly of West African ancestry, with minimal European and Native American admixture. The Tobago population, thus, may carry a higher burden of high-risk alleles of African origin for certain diseases than the more admixed African-American population. Conversely, this population may benefit from a higher prevalence of protective alleles of African origin.

Black People↗

Nuclear receptor coactivator-3 alleles are associated with serum bioavailable testosterone, insulin-like growth factor-1, and vertebral bone mass in men.

CONTEXT: Nuclear receptor coactivator-3 (NCOA3) is a member of the steroid receptor coactivator family that interacts with nuclear hormone receptors to enhance their transcriptional activation function and may play a role in somatic growth. OBJECTIVE: The aim of this study was to examine the relationships between the CAG/CAA (glutamine) length variation at the NCOA3 locus, sex steroid hormone, and IGF-I levels and bone mineral density (BMD) in a cohort of older Caucasian men. DESIGN AND METHODS: We analyzed the association between potentially functional alleles at this locus, serum sex steroid hormone, and IGF-I levels and lumbar spine and proximal femur BMD (Hologic QDR) in 263 community-dwelling Caucasian men (age 66 +/- 7 yr, mean +/- sd; range 51-84 yr). Men were genotyped for a CAG/CAA repeat polymorphism in NCOA3, which encodes a polyglutamine tract of variable length in the C-terminal transcriptional activation domain of the protein. RESULTS: We found a significant monotonic decrease in lumbar spine, but not hip, BMD with increasing copies of the most common allele (29 repeats, 53%). For example, men with the 29/29 genotype had 6% or nearly 0.5 sd lower spine BMD than men without this genotype, and NCOA3 genotype explained 3.2% of the phenotypic variation in this trait. Serum levels of bioavailable testosterone and IGF-I paralleled genotype-related differences in lumbar spine BMD. CONCLUSION: Allelic variation at the NCOA3 locus may contribute to the genetic control of androgenic hormone and IGF levels and vertebral bone mass among older men.

Acetyltransferases↗

Susceptibility genes for age-related maculopathy on chromosome 10q26.

On the basis of genomewide linkage studies of families affected with age-related maculopathy (ARM), we previously identified a significant linkage peak on 10q26, which has been independently replicated by several groups. We performed a focused SNP genotyping study of our families and an additional control cohort. We identified a strong association signal overlying three genes, PLEKHA1, LOC387715, and PRSS11. All nonsynonymous SNPs in this critical region were genotyped, yielding a highly significant association (P < .00001) between PLEKHA1/LOC387715 and ARM. Although it is difficult to determine statistically which of these two genes is most important, SNPs in PLEKHA1 are more likely to account for the linkage signal in this region than are SNPs in LOC387715; thus, this gene and its alleles are implicated as an important risk factor for ARM. We also found weaker evidence supporting the possible involvement of the GRK5/RGS10 locus in ARM. These associations appear to be independent of the association of ARM with the Y402H allele of complement factor H, which has previously been reported as a major susceptibility factor for ARM. The combination of our analyses strongly implicates PLEKHA1/LOC387715 as primarily responsible for the evidence of linkage of ARM to the 10q26 locus and as a major contributor to ARM susceptibility. The association of either a single or a double copy of the high-risk allele within the PLEKHA1/LOC387715 locus accounts for an odds ratio of 5.0 (95% confidence interval 3.2-7.9) for ARM and a population attributable risk as high as 57%.

Case-Control Studies↗

NADPH oxidase p22phox gene variants are associated with systemic oxidative stress biomarker responses to exercise training.

Systemic oxidative stress plays a role in many degenerative diseases. Although regular physical activity has been known as the most effective nonpharmacological intervention to alleviate the oxidative stress, the beneficial effect varies between individuals. We investigated whether NADPH oxidase p22phox gene C242T and A640G polymorphisms are associated with systemic oxidative stress level response to exercise training (ExTr). Fifty-nine sedentary middle-aged to older Caucasians with relatively high cardiovascular disease risk factors underwent a 6-mo standardized ExTr program. Body mass index, plasma lipoprotein-lipid profiles, cardiovascular fitness, and plasma thiobarbituric acid reactive substances (TBARS) were measured before and after ExTr. Demographic and initial levels of cardiovascular disease risk factors were similar among genotype groups for both polymorphisms. Overall, TBARS was decreased by 16% with ExTr in the entire group (P < 0.001). There was no significant difference in TBARS changes with ExTr among the C242T genotype groups. However, A allele carriers showed greater reduction in TBARS than noncarriers at the A640G locus (P = 0.05). There was a significant interaction (P = 0.05) between ExTr and A640G polymorphism in TBARS changes with ExTr. This interaction remained after accounting for age and baseline TBARS level. Furthermore, diplotype analysis showed that TBARS was decreased to a greater extent in the C242/A640 haplotype carriers compared with the noncarriers (P < 0.05). We found that p22phox polymorphisms, especially A640G, were associated with differential changes in systemic oxidative stress with aerobic exercise training.

Aged↗

Candidate gene analysis suggests a role for fatty acid biosynthesis and regulation of the complement system in the etiology of age-related maculopathy.

Age-related maculopathy (ARM) is a leading cause of visual impairment in elderly Americans and is a complex genetic disorder. Hypothesized pathways for the etiology of ARM include cholesterol and lipoprotein metabolism and transport, extracellular matrix integrity, oxidative stress and inflammatory/immunologic processes. This study investigates 21 polymorphisms within 15 candidate genes whose products function within these pathways by performing family and case-control genetic association studies using clearly affected familial cases (n=338 families, 796 individuals), clearly affected, unrelated sporadic cases (n=196) and clearly unaffected, unrelated controls (n=120). Two genes demonstrated significant association with ARM status. A Met299Val variant in the elongation of very long chain fatty acids-like 4 (ELOVL4) gene was significantly associated with ARM in the case-control allele (P=0.001), case-control genotype (P=0.001) and case-control family (P<0.0001) tests. A Tyr402His variant in exon 9 in the complement factor H (CFH) gene was also significantly associated with ARM in the case-control allele (P<0.0001), case-control genotype (P<0.0001) and case-control family (P<0.0001) tests. All of these results remain significant after adjusting for false discovery rates to control for the impact of multiple testing. In addition, the CFH variant appears to play a role in exudative and atrophic disease, whereas the ELOVL4 variant may play a greater role in exudative disease in our population. These results support a potential role for multiple pathways in the etiology of ARM, including pathways involved with fatty acid biosynthesis and the complement system.

Aging↗

Vitamin D receptor FokI genotype influences bone mineral density response to strength training, but not aerobic training.

To determine the influence of the vitamin D receptor (VDR) gene FokI and BsmI genotype on bone mineral density response to two exercise training modalities, 206 healthy men and women (50-81 years old) were studied before and after approximately 5-6 months of either aerobic exercise training (AT) or strength training (ST). A totla of 123 subjects completed AT (51 men, 72 women) and 83 subjects completed ST (40 men, 43 women). DNA was extracted from blood samples of all subjects and genotyping was performed at the VDR FokI and BsmI locus to determine its association to training response. Total body, greater trochanter and femoral neck bone mineral density (BMD) were measured before and after both training programmes using dual-energy X-ray absorptiometry. VDR BsmI genotype was not significantly related to BMD at baseline or after ST or AT. However, VDR FokI genotype was significantly related to ST- but not AT-induced changes in femoral neck BMD (P < 0.05). The heterozygotes (Ff) in the ST group approached a significantly greater increase in femoral neck BMD (P = 0.058) compared to f homozygotes. There were no significant genotype relationships in the AT group. These data indicate that VDR FokI genotype may influence femoral neck BMD response to ST, but not AT.

Absorptiometry, Photon↗

Interleukin-6 genotype is associated with high-density lipoprotein cholesterol responses to exercise training.

BACKGROUND: High-density lipoprotein cholesterol (HDL-C) and its subfractions are modifiable with exercise training and these responses are heritable. The interleukin-6 (IL6)-174G/C polymorphism may be associated with HDL-C levels. We hypothesized that the IL6-174G/C polymorphism would be associated with plasma HDL-C response to exercise training. METHODS AND RESULTS: Sixty-five 50- to 75-year-olds on a standardized diet were studied before and after 24 weeks of aerobic exercise training. Significant differences existed among genotype groups for change with exercise training in HDL-C, HDL3-C, integrated HDL4,5NMR-C, and HDLsize. The CC genotype group increased HDL-C more than the GG (7.0 +/- 1.3 v. 1.0 +/- 1.1 mg/dL, p = 0.001) and GC groups (3.3 +/- 0.9 mg/dL, p = 0.02); for HDL3-C, the CC group increased more than the GG (6.1 +/- 1.0 v. 0.9 +/- 0.9, mg/dL p < 0.001) and GC groups (2.5 +/- 0.7 mg/dL, p = 0.006). Integrated HDL4,5NMR-C increased more in the CC than GG group (6.5 +/- 1.6 mg/dL v. 1.0 +/- 1.3 mg/dL, p = 0.01), as did HDLsize compared to the GG (CC: 0.3 +/- 0.1 v. GG: 0.1 +/- 0.1 nm, p = 0.02) and GC (0.0 +/- 0.0 nm, p = 0.007) groups. CONCLUSIONS: IL6 genotype is associated with HDL-C response to exercise training.

Aged↗

Identification of a novel 5-base pair deletion in calcineurin B (PPP3R1) promoter region and its association with left ventricular hypertrophy.

BACKGROUND: Calcineurin is a calcium/calmodulin-regulated protein phosphatase that functions as a key mediator of hypertrophic response of the heart. Calcineurin B (CnB) is a regulatory subunit of calcineurin and is important for the phosphatase activity. METHODS: We identified a novel 5-base pair (bp) insertion/deletion (5I/5D) polymorphism within the CnB promoter region and investigated its association with left ventricular hypertrophy (LVH) in 368 severe hypertensive participants (53% African Americans) in the Hypertension Genetic Epidemiology Network study. Traditionally defined LVH was identified by LV mass index >50 g/m(2.7) in men and >47 g/m(2.7) in women. Left ventricular mass predicted from sex, stroke work, and height(2.7) was calculated according to an equation derived from a normal population, and inappropriately high LV mass was defined as observed/predicted LV mass >1.28 based on the equation. RESULTS: The CnB 5I/5D variation was not significantly associated with the traditionally defined LVH. However, there was a significant association between the CnB 5I/5D polymorphism and presence of inappropriately high LV mass. The ethnicity-adjusted ORs for the 5I/5D and 5D/5D genotypes compared with the 5I/5I genotype was 1.23 (95% CI 0.66-2.28) and 3.05 (95% CI 1.28-7.29) (P = .02 for trend test). This association was independent of age, sex, body mass index, heart rate, prevalent coronary heart disease, and/or diabetes and antihypertensive medications. CONCLUSIONS: The 5-base pair deletion within the CnB gene may cause excessive LV growth beyond the level appropriate for cardiac workload when exposed to severe hypertension or may be in linkage disequilibrium with the causal mutation.

Black or African American↗

Association between allelic variants in cytokine genes and preeclampsia.

OBJECTIVE: The purpose of this study was to examine the relationship between cytokine genotypes and preeclampsia. STUDY DESIGN: We conducted a case-control study that examined cytokine genotypes among 150 primiparous preeclamptic women and 661 primiparous, normotensive women. Analyses were adjusted for age, prepregnancy cigarette smoking, and education. RESULTS: Preeclamptic white women were more likely than normotensive white women to carry the up-regulating tumor necrosis factor-alpha-308 A/A (odds ratio, 4.1; 95% CI, 1.1-15.3) genotype. Both black and white women with preeclampsia were more likely than normotensive control subjects to carry the interleukin-1alpha-producing-4845 G/G genotype (black odds ratio, 11.6; 95% CI, 1.5-89.3; white odds ratio, 1.7; 95% CI, 0.7-3.9), -889 C/C genotype (black odds ratio, 5.1; 95% CI, 0.6-41.6; white odds ratio, 1.9; 95% CI, 0.8-4.7), and the interleukin-1alpha-4845/interleukin-1alpha-889/interleukin-1beta-3957 GCC/GCC haplotype (black odds ratio, 3.4; 95% CI, 1.3-8.7; white odds ratio, 2.1; 95% CI, 1.4-3.2). CONCLUSION: Cytokine genotypes were associated with preeclampsia and may identify women who are at high risk for preeclampsia.

Adult↗

Genome-wide linkage study of erythrocyte sodium-lithium countertransport.

BACKGROUND: Increased erythrocyte sodium-lithium countertransport (SLC) has been observed in patients with essential hypertension. An analytic strategy for identification of genetic variation contributing to hypertension is the evaluation of appropriate intermediate phenotypes for hypertension, such as SLC. Thus, in this study, genome-wide linkage scans for SLC were performed in two independent samples of pedigrees from the Rochester Family Heart Study (RFHS). METHODS: Genome-wide linkage scans for SLC were performed in independent samples of 232 and 252 non-Hispanic white families from the RFHS. Multipoint variance-component linkage analysis was performed using MERLIN. RESULTS: Chromosomes 8, 9, 10, 19, and 20 contained evidence for linkage (log of the odds [LOD] > or =2) in at least one sample of RFHS pedigrees. Consistent evidence of linkage for SLC between the two samples was observed on chromosome 10 (LOD = 2.02 at 64 cM in the first sample and LOD = 2.27 at 55 cM in the second sample). CONCLUSIONS: Consistent evidence of linkage (LOD > or =2) for SLC was observed in two independent samples of non-Hispanic white families on chromosome 10. Concordance of linkage evidence between the two samples provides confidence that a region on chromosome 10 contains genetic variation influencing SLC, which may potentially influence susceptibility to hypertension.

Antiporters↗

The C161-->T polymorphism in peroxisome proliferator-activated receptor gamma, but not P12A, is associated with insulin resistance in Hispanic and non-Hispanic white women: evidence for another functional variant in peroxisome proliferator-activated receptor gamma.

The P12A variant in the peroxisome proliferator-activated receptor gamma (PPARgamma) gene has been intensely studied for association with obesity-related or type-2 diabetes-related traits; however, the results have been somewhat inconsistent in different populations. We genotyped a large cohort of Hispanic and non-Hispanic white individuals from the San Luis Valley Diabetes Study for P12A and another common variant, C161-->T, in the PPARgamma gene to determine if these sites were associated with fasting glucose, insulin, free fatty acid levels, insulin sensitivity, or body fat. There were no statistically significant frequency differences at these two sites between Hispanic and non-Hispanic individuals. No significant association with the metabolic phenotypes was observed for either of the polymorphisms in men; however, in women, significant associations were shown between the C161-->T variant and fasting insulin (P=.008) and the homeostasis model assessment of insulin resistance (HOMA IR; P=.007). After adjusting for age, smoking, fat mass, and skin reflectance, linear regression showed that C161-->T explained 1.5% of the variation in both fasting insulin (P=.031) and HOMA IR (P=.028) whereas P12A contributed only 0.04% (fasting insulin, P=.268) and 0.02% (HOMA IR, P=.418) to the total trait variation. In the San Luis Valley Diabetes Study female patients, C161-->T appears to be a better predictor of fasting insulin levels and insulin resistance than P12A although the effect of this variant is small. These results support the hypothesis that C161-->T is in linkage disequilibrium with unidentified functional variation in PPARgamma or in a linked gene. This could explain some of the inconsistencies in the P12A association studies as the allele frequency and level of linkage disequilibrium of another functional polymorphism in the region could vary in different populations.

Colorado↗

The socio-economic status of communities predicts variation in brain serotonergic responsivity.

BACKGROUND: We reported previously that the socio-economic status (SES) of individuals predicts variation in brain serotonergic responsivity, as assessed by neuropharmacological challenge in an adult community sample, and that this association is qualified by allelic variation in the serotonin transporter gene-linked polymorphic region (5-HTTLPR). Here we examine whether serotonergic responsivity covaries similarly with the SES of communities, as indexed by US Census data in the same study sample. METHOD: Community SES was defined by levels of income, economic disadvantage, housing costs, and educational attainment of census tracts in which 249 locally recruited study participants (54% male) resided. Serotonergic responsivity was assessed as the baseline-adjusted, peak plasma prolactin (Prl) concentration following acute administration of the serotonin-releasing agent, fenfluramine; tissue for DNA extraction and 5-HTTLPR genotyping was available on 131 participants. RESULTS: Subjects residing in census tracts of lower SES showed a blunted Prl response to fenfluramine (diminished serotonergic responsivity) relative to individuals living in more affluent neighborhoods. When adjusted for personal income and education, SES at the community level continued to predict fenfluramine-stimulated Prl responses and did so independently of 5-HTTLPR genotype. CONCLUSIONS: Area-level indices of relative social and economic disadvantage covary with individual differences in brain serotonergic responsivity, and this association is, in part, independent of individually defined SES. These findings may be relevant to reported effects of low community SES on the prevalence of psychiatric disorders or behaviors associated with dysregulation of central serotonergic function, such as depression, impulsive aggression, and suicide.

Adult↗

Blood pressure response to strength training may be influenced by angiotensinogen A-20C and angiotensin II type I receptor A1166C genotypes in older men and women.

OBJECTIVES: To determine the influence of angiotensinogen (AGT) A-20C, M235 T, and angiotensin II type 1 receptor (AGTR1) A1166C genotypes on resting blood pressure (BP) response to strength training (ST) in older men and women. DESIGN: Prospective intervention study with retrospective genotyping. SETTING: University of Maryland Exercise Physiology Laboratory. PARTICIPANTS: Seventy sedentary, healthy older men (n=34) and women (n=36). INTERVENTION: Approximately 23 weeks of ST performed 3 days per week. MEASUREMENTS: Resting BP was measured on six separate occasions before and after ST for each subject. AGT and AGTR1 genotyping was performed retrospectively from each subject's genomic deoxyribonucleic acid. RESULTS: Systolic BP decreased in C-allele carriers at the AGT A-20C locus with ST (122+/-1 to 116+/-2 mmHg, P<.05), which was significantly greater than the decrease in the A homozygotes (126+/-1 to 123+/-1 mmHg, P<.05). At the AGTR1 A1166C locus, diastolic BP decreased to a greater extent in the C-allele carriers (76+/-1 to 70+/-2 mmHg, P<.05) than in the A homozygotes (75+/-1 to 72+/-1 mmHg, P<.05). CONCLUSION: The AGT A-20C and AGTR1 A1166C genotypes may influence resting BP response to ST, such that C-allele carriers at each of these loci reduce their resting BP in response to ST to a greater extent than A homozygotes.

Aged↗

Muscle strength response to strength training is influenced by insulin-like growth factor 1 genotype in older adults.

Strength training (ST) is considered an intervention of choice for the prevention and treatment of sarcopenia. Reports in the literature have suggested that the insulin-like growth factor I protein (IGF-I) plays a major role in ST-induced skeletal muscle hypertrophy and strength improvements. A microsatellite repeat in the promoter region of the IGF1 gene has been associated with IGF-I blood levels and phenotypes related to IGF-I in adult men and women. To examine the influence of this polymorphism on muscle hypertrophic and strength responses to ST, we studied 67 Caucasian men and women before and after a 10-wk single-leg knee-extension ST program. One repetition maximum strength, muscle volume via computed tomography, and muscle quality were assessed at baseline and after 10 wk of training. The IGF1 repeat promoter polymorphism and three single-nucleotide polymorphisms were genotyped. For the promoter polymorphism, subjects were grouped as homozygous for the 192 allele, heterozygous, or noncarriers of the 192 allele. After 10 wk of training, 1-repetition maximum, muscle volume, and muscle quality increased significantly for all groups combined (P < 0.001). However, carriers of the 192 allele gained significantly more strength with ST than noncarriers of the 192 allele (P = 0.02). There was also a nonsignificant trend for a greater increase in muscle volume in 192 carriers than noncarriers (P = 0.08). No significant associations were observed for the other polymorphisms studied. Thus these data suggest that the IGF1 promoter polymorphism may influence the strength response to ST. Larger sample sizes should be used in future studies to verify these results.

Aged↗

Comparative gene expression analysis of ovarian carcinoma and normal ovarian epithelium by serial analysis of gene expression.

Despite the poor prognosis of ovarian cancer and the importance of early diagnosis, there are no reliable noninvasive biomarkers for detection in the early stages of disease. Therefore, to identify novel ovarian cancer markers with potential utility in early-stage screening protocols, we have undertaken an unbiased and comprehensive analysis of gene expression in primary ovarian tumors and normal human ovarian surface epithelium (HOSE) using Serial Analysis of Gene Expression (SAGE). Specifically, we have generated SAGE libraries from three serous adenocarcinomas of the ovary and, using novel statistical tools, have compared these to SAGE data derived from two pools of normal HOSE. Significantly, in contrast to previous SAGE-based studies, our normal SAGE libraries are not derived from cultured cell lines. We have also compared our data with publicly available SAGE data obtained from primary tumors and "normal" HOSE-derived cell lines. We have thus identified several known and novel genes whose expressions are elevated in ovarian cancer. These include but are not limited to CLDN3, WFDC2, FOLR1, COL18A1, CCND1, and FLJ12988. Furthermore, we found marked differences in gene expression patterns in primary HOSE tissue compared with cultured HOSE. The use of HOSE tissue as a control for these experiments, along with hierarchical clustering analysis, identified several potentially novel biomarkers of ovarian cancer, including TACC3, CD9, GNAI2, AHCY, CCT3, and HMGA1. In summary, these data identify several genes whose elevated expressions have not been observed previously in ovarian cancer, confirm the validity of several existing markers, and provide a foundation for future studies in the understanding and management of this disease.

Adult↗

Association of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) genotype with depression in elderly persons after hip fracture.

OBJECTIVE: The authors examined the serotonin transporter gene-linked polymorphic region (5-HTTLPR) as a predictor of major depressive disorder and depressive symptoms after hip fracture, a common stressful medical event. METHODS: This was a prospective, observational study of 23 elderly rehabilitation-hospital patients during their inpatient stay. Depressive symptoms were assessed by Hamilton Rating Scale for Depression (Ham-D) and PRIME-MD. Subjects were also genotyped for 5-HTTLPR. RESULTS: Survival analysis showed that genotype significantly predicted time-to-major depressive episode. Subjects with an s allele (genotype s/l or s/s) had significantly higher Ham-D scores over 14 weeks of follow-up than those with the l/l genotype. CONCLUSION: Depressive symptoms and major depressive disorder in elderly persons after a stressful medical event may be associated with 5-HTTLPR genotype. This finding requires confirmation in a larger sample.

Aged↗

Deficiency of subsarcolemmal mitochondria in obesity and type 2 diabetes.

The current study addresses a novel hypothesis of subcellular distribution of mitochondrial dysfunction in skeletal muscle in type 2 diabetes. Vastus lateralis muscle was obtained by percutaneous biopsy from 11 volunteers with type 2 diabetes; 12 age-, sex-, and weight-matched obese sedentary nondiabetic volunteers; and 8 lean volunteers. Subsarcolemmal and intermyofibrillar mitochondrial fractions were isolated by differential centrifugation and digestion techniques. Overall electron transport chain activity was similar in type 2 diabetic and obese subjects, but subsarcolemmal mitochondria electron transport chain activity was reduced in type 2 diabetic subjects (0.017 +/- 0.003 vs. 0.034 +/- 0.007 units/mU creatine kinase [CK], P = 0.01) and sevenfold reduced compared with lean subjects (P < 0.01). Electron transport chain activity in intermyofibrillar mitochondria was similar in type 2 diabetic and obese subjects, though reduced compared with lean subjects. A reduction in subsarcolemmal mitochondria was confirmed by transmission electron microscopy. Although mtDNA was lower in type 2 diabetic and obese subjects, the decrement in electron transport chain activity was proportionately greater, indicating functional impairment. Because of the potential importance of subsarcolemmal mitochondria for signal transduction and substrate transport, this deficit may contribute to the pathogenesis of muscle insulin resistance in type 2 diabetes.

Adult↗

Effects of weight loss and physical activity on skeletal muscle mitochondrial function in obesity.

The current study was undertaken to address responsiveness of skeletal muscle mitochondrial electron transport chain (ETC) activity to weight loss (WL) and exercise in overweight or obese, sedentary volunteers. Fourteen middle-aged participants (7 male/7 female) had assessments of mitochondrial ETC activity and mitochondrial (mt)DNA in vastus lateralis muscle, obtained by percutaneous biopsy, before and after a 16-wk intervention. Mean WL was 9.7 (1.5%) and the mean increase in Vo(2 max) was [means (SD)] 21.7 (3.7)%. Total ETC activity increased significantly, from 0.13 (0.02) to 0.19 (0.03) U/mU creatine kinase (CK; P < 0.001). ETC activity was also assessed in mitochondria isolated into subsarcolemmal (SSM) and intermyofibrillar (IMF-M) fractions. In response to intervention, there was a robust increase of ETC activity in SSM (0.028 (0.007) to 0.046 (0.011) U/mU CK, P < 0.001), and in IMF-M [0.101 (0.015) to 0.148 (0.018) U/mU CK, P < 0.005]. At baseline, the percentage of ETC activity contained in the SSM fraction was low and remained unchanged following intervention [19 (3) vs. 22 (2)%], despite the increase in ETC activity. Also, muscle mtDNA content did not change significantly [1665 (213) vs. 1874 (214) mtDNA/nuclear DNA], denoting functional improvement rather than proliferation of mitochondria as the principal mechanism of enhanced ETC activity. Increases in ETC activity were correlated with energy expenditure during exercise sessions, and ETC activity in SSM correlated with insulin sensitivity after adjustment for Vo(2 max). In summary, skeletal muscle ETC activity is increased by WL and exercise in previously sedentary obese men and women. We conclude that improved skeletal muscle ETC activity following moderate WL and improved aerobic capacity contributes to associated alleviation of insulin resistance.

Adult↗