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Papers by Alice Ryan

The Journals of Gerontology, Dec 19, 2013

The purpose of this study was to determine the effects of 6-month aerobic exercise training + wei... more The purpose of this study was to determine the effects of 6-month aerobic exercise training + weight loss (AEX + WL) on basal and insulin activation of glycogen synthase, basal citrate synthase activity, and Akt and AS160 phosphorylation in older, overweight/obese insulin-resistant men (n = 14; 63 ± 2 years; body mass index, 32 ± kg/m 2). Muscle samples of the vastus lateralis were collected before and during a 3-hour 80 mU/m 2 /min hyperinsulinemic-euglycemic clamp. AEX + WL increased VO 2max by 11% (p < .05) and decreased body weight (−9%, p < .001). AEX + WL increased basal citrate synthase activity by 46% (p < .01) and insulin activation of independent (2.9-fold) and fractional (2.3-fold) activities (both p < .001) of glycogen synthase. AEX + WL had no effect on phosphorylation of Akt or AS160. Glucose utilization (M) improved 25% (p < .01), and the change tended to be related to the increase in insulin activation of glycogen synthase fractional activity (r = .50, p = .08) following AEX + WL. In summary, AEX + WL has a robust effect on insulin activation of skeletal muscle glycogen synthase activity that likely contributes to improved glucose utilization in older insulin-resistant men.

Obesity, Feb 1, 2011

The β 2-adrenergic receptor (ADRB2) mediates obesity, cardiorespiratory fitness, and insulin resi... more The β 2-adrenergic receptor (ADRB2) mediates obesity, cardiorespiratory fitness, and insulin resistance. We examined the hypothesis that ADRB2 Arg16Gly-Gln27Glu haplotype is associated with body composition, glucose tolerance, and insulin sensitivity in obese, postmenopausal women. Obese (>35% body fat), postmenopausal (age 45-75 years) women (n = 123) underwent genotyping, dual-energy X-ray absorptiometry, and computed tomography scans, exercise testing (VO 2 max), 2-h oral glucose tolerance tests (OGTTs), and hyperinsulinemic-euglycemic clamps (80 mU/m 2 /min). Analysis of covariance (ANCOVA) tested for differences among haplotypes, with race, % body fat, and VO 2 max as covariates. We found that ADRB2 haplotype was independently associated with % body fat, abdominal fat distribution, VO 2 max , insulin sensitivity (M/ΔInsulin), and glucose tolerance (ANOVA, P < 0.05 for all). Women homozygous for Gly16-Gln27 haplotype had the highest % body fat (52.7 ± 1.9%), high abdominal fat, low M/ΔInsulin (0.49 ± 0.08 mg/kg/min/pmol/l/10 2), and impaired glucose tolerance (IGT) during an OGTT (G 120 = 10.2 ± 0.9 mmol/l). Women homozygous for Gly16-Glu27 haplotype also had low M/ΔInsulin (0.51 ± 0.05 mg/kg/min/pmol/l/10 2) and IGT (G 120 = 8.2 ± 0.7 mmol/l). Subjects with Arg16-Gln27/Gly16-Gln27 haplotype combination had the highest VO 2 max (1.84 ± 0.07 l/min) and M/ ΔInsulin (0.7 ± 0.04 mg/kg/min/pmol/l/10 2), and normal glucose tolerance (G 120 = 6.4 ± 0.4 mmol/l), despite being obese. These data show associations of the ADRB2 Arg16Gly-Gln27Glu haplotype with VO 2 max and body composition, and an independent association with glucose metabolism, which persists after controlling for body composition and fitness. This suggests that ADRB2 haplotypes may mediate insulin action, glucose tolerance, and potentially risk for type 2 diabetes mellitus (T2DM) in obese, postmenopausal women.

Journal of Applied Physiology, Feb 1, 2002

The purpose of the present study was to determine whether age, sex, or angiotensin I-converting e... more The purpose of the present study was to determine whether age, sex, or angiotensin I-converting enzyme (ACE) genotype influences the effects of strength training (ST) on glucose homeostasis. Nineteen sedentary young (age ϭ 20-30 yr) men (n ϭ 10) and women (n ϭ 9) were studied and compared with 21 sedentary older (age ϭ 65-75 yr) men (n ϭ 12) and women (n ϭ 9) before and after a 6-mo total body ST program. Fasting insulin concentrations were reduced in young men and in older men with ST (P Ͻ 0.05 in both). In addition, total insulin area under the curve decreased by 21% in young men (P Ͻ 0.05), and there was a trend for a decrease (11%) in older men (P ϭ 0.06). No improvements in insulin responses were observed in young or older women. The ACE deletion/deletion genotype group had the lowest fasting insulin and insulin areas under the oral glucose tolerance test (OGTT) curve before training (all P Ͻ 0.05), but those with at least one insertion allele had a trend for a greater reduction in total insulin area than deletion homozygotes (P ϭ 0.07). These results indicate that ST has a more favorable effect on insulin response to an OGTT in men than in women and offer some support for the hypothesis that ACE genotype may influence insulin responses to ST.

Diabetes Care, Apr 10, 2014

Transcapillary transport of insulin is one determinant of glucose uptake by skeletal muscle; thus... more Transcapillary transport of insulin is one determinant of glucose uptake by skeletal muscle; thus, a reduction in capillary density (CD) may worsen insulin sensitivity. Skeletal muscle CD is lower in older adults with impaired glucose tolerance (IGT) compared with those with normal glucose tolerance and may be modifiable through aerobic exercise training and weight loss (AEX+WL). We tested the hypothesis that 6-month AEX+WL would increase CD to improve insulin sensitivity and glucose tolerance in older adults with IGT. RESEARCH DESIGN AND METHODS Sixteen sedentary, overweight-obese (BMI 27-35 kg/m 2), older (63 6 2 years) men and women with IGT underwent hyperinsulinemic-euglycemic clamps to measure insulin sensitivity, oral glucose tolerance tests, exercise and body composition testing, and vastus lateralis muscle biopsies to determine CD before and after 6-month AEX+WL. RESULTS Insulin sensitivity (M) and 120-min postprandial glucose (G 120) correlated with CD at baseline (r = 0.58 and r = 20.60, respectively, P < 0.05). AEX+WL increased maximal oxygen consumption (VO 2max) 18% (P = 0.02) and reduced weight and fat mass 8% (P < 0.02). CD increased 15% (264 6 11 vs. 304 6 14 capillaries/mm 2 , P 5 0.01), M increased 21% (42.4 6 4.0 vs. 51.4 6 4.3 mmol/kg FFM/min, P < 0.05), and G 120 decreased 16% (9.35 6 0.5 vs. 7.85 6 0.5 mmol/L, P = 0.008) after AEX+WL. Regression analyses showed that the AEX+WL-induced increase in CD independently predicted the increase in M (r = 0.74, P < 0.01) as well as the decrease in G 120 (r = 20.55, P < 0.05). CONCLUSIONS Six-month AEX+WL increases skeletal muscle CD in older adults with IGT. This represents one mechanism by which AEX+WL improves insulin sensitivity in older adults with IGT.

Archives of Physical Medicine and Rehabilitation, Mar 1, 2017

Objective-To determine the prevalence of sarcopenia in stroke survivors using different methodolo... more Objective-To determine the prevalence of sarcopenia in stroke survivors using different methodologies and compared a subset of the stroke group to age, sex, and BMI-matched nonstroke control counterparts. Design-Cohort Study Setting-Veterans Affairs Medical Center and University Hospital Participants-Mild to moderately disabled chronic participants with stroke aged 40-84 yrs (n=190, 61% male, 57% African American, BMI: 29±1 kg/m 2 , X±SEM) Interventions-Not applicable Main Outcome Measures-DXA scans to assess appendicular lean mass (ALM). Rates of sarcopenia were determined using four established methods: 1) ALM/ht 2 ; 2) European Working Group on Sarcopenia in Older Persons; 3) International Working Group on Sarcopenia; and 4) ALM/BMI. Results-Sarcopenia prevalence in our stroke cohort ranged between 14% and 18%. The stroke survivor subset (n=38) matched one-for-one with control counterparts for race, sex, age±4 years and BMI±2.5 units had higher prevalence rates compared to their non-stroke counterparts (13.2% vs. 5.3%, P<0.0001). ALM/ht 2 was related to six-minute walking speed (r=0.28, P<0.01) and VO 2 peak (l/min r=0.58, P<0.0001) for the stroke group.

Neurorehabilitation and Neural Repair, Jul 6, 2011

Purpose-Sarcopenia and increased fat infiltration in muscle may play a role in the functional imp... more Purpose-Sarcopenia and increased fat infiltration in muscle may play a role in the functional impairment and high risk for diabetes in stroke. Our purpose was to compare muscle volume and muscle attenuation across 6 muscles of the paretic and nonparetic thigh and examine the relationships between intramuscular fat and insulin resistance and between muscle volume and strength in stroke patients. Methods-Stroke participants (70; 39 men, 31 women) aged 40 to 84 years, BMI = 16 to 45 kg/ m 2 underwent multiple thigh CT scans, total body scan by DXA (dual-energy X-ray absorptiometry), peak oxygen intake (VO 2peak) graded treadmill test, 6-minute walk, fasting blood draws, and isokinetic strength testing. Results-Muscle volume is 24% lower and subcutaneous fat volume is 5% higher in the paretic versus nonparetic thigh. Muscle attenuation (index of amount of fat infiltration in muscle) is 17% higher in the nonparetic midthigh than the paretic. The semitendinosis/semimembranosis, biceps femoris, sartorius, vastus (medialis/lateralis), and rectus femoris have lower (between 9% and 19%) muscle areas on the paretic than the nonparetic thigh. Muscle attenuation is 15% to 25% higher on the nonparetic than the paretic side for 5 of 6 muscles. The nonparetic midthigh muscle attenuation is negatively associated with insulin. Eccentric peak torque of the nonparetic leg and paretic leg are associated with the corresponding muscle volume. Conclusions-The skeletal muscle atrophy, increased fat around and within muscle, and ensuing muscular weakness observed in chronic stroke patients relates to diabetes risk and may impair functional mobility and independence.

The Journals of Gerontology, May 1, 2006

Background. Aging is associated with insulin resistance, primarily as a result of physical inacti... more Background. Aging is associated with insulin resistance, primarily as a result of physical inactivity and increased abdominal obesity. We hypothesized that aerobic (AEX) or resistive (RT) exercise training would result in comparable improvements in glucose disposal in older men, but that there would be different metabolic adaptations in skeletal muscle. Methods. Thirty-nine older (63 6 1 years, mean 6 standard error of the mean), overweight and obese (body mass index ¼ 30.3 6 0.4 kg/m 2) men were assigned to AEX (treadmill walking and/or jogging, n ¼ 19) or RT (upper and lower body, n ¼ 20) programs 3 d/wk for 6 months, with 9 completing AEX and 13 completing RT. Testing before and after the exercise programs included body composition, euglycemic-hyperinsulinemic clamps, and vastus lateralis muscle biopsies. Results. Maximal oxygen consumption (VO 2max) increased by 16% after AEX (p , .01), while leg and arm muscle strength increased by 45 6 5% and 27 6 5% after RT (p , .0001). Although participants were monitored to maintain their body weight during the exercise program, body weight decreased by 2% after AEX (p , .05), and increased by 2% after RT (p , .05). Whole-body glucose disposal, determined during the last 30 minutes of a 2-hour 480 pmol/m 2 /min euglycemic-hyperinsulinemic clamp, increased comparably by 20%-25% after AEX (51 6 5 to 61 6 5 lM/kg fat-free mass / min, p , .05) and RT (49 6 3 to 58 6 3 lM/kg fat-free mass /min, p , .05). The increase in vastus lateralis muscle glycogen synthase fractional activity in response to insulin stimulation was significantly higher after AEX compared to after RT (279 6 59% compared to 100 6 28% change, p , .05). Neither AEX nor RT altered muscle glycogen synthase total activity, glycogen content, or levels of phosphotidylinositol 3-kinase. Conclusion. These results suggest that AEX and RT result in comparable improvements in glucose metabolism in older men, whereas an increase in insulin activation of glycogen synthase occurred only with AEX. These improvements in insulin sensitivity could reduce the risk of metabolic syndrome and type 2 diabetes and attenuate the development of cardiovascular disease.

Frontiers in rehabilitation sciences, Feb 24, 2022

Exercise training is an essential component in the treatment or rehabilitation of various disease... more Exercise training is an essential component in the treatment or rehabilitation of various diseases and conditions. However, barriers to exercise such as the burdens of travel or time may hinder individuals' ability to participate in such training programs. Advancements in technology have allowed for remote, home-based exercise training to be utilized as a supplement or replacement to conventional exercise training programs. Individuals in these home-based exercise programs are able to do so under varying levels of supervision from trained professionals, with some programs having direct supervision, and others having little to no supervision at all. The purpose of this review is to examine the use of home-based, tele-exercise training programs for the treatment of different disease states and conditions, and how these programs compare to conventional clinic-based exercise training programs.

Journal of stroke and cerebrovascular diseases, Dec 1, 2019

Background: Understanding the metabolic response to exercise may aid in optimizing stroke managem... more Background: Understanding the metabolic response to exercise may aid in optimizing stroke management. Therefore, the purpose of this pilot study was to evaluate plasma metabolomic profiles in chronic stroke survivors following aerobic exercise training. Methods: Participants (age: 62 ± 1 years, body mass index: 31 ± 1 kg/m 2 , mean ± standard error of the mean) were randomized to 6 months of treadmill exercise (N = 17) or whole-body stretching (N = 8) with preintervention and postintervention measurement of aerobic capacity (VO 2 peak). Linear models for microarray data expression analysis was performed to determine metabolic changes over time, and Mummichog was used for pathway enrichment analysis following analysis of plasma samples by high-performance liquid chromatography coupled to ultrahigh resolution mass spectrometry. Results: VO 2 peak change was greater following exercise than stretching (18.9% versus −.2%; P < .01). Pathway enrichment analysis of differentially expressed metabolites results showed significant enrichment in 4 pathways following treadmill exercise, 3 of which (heparan-, chondroitin-, keratan-sulfate degradation) involved connective tissue metabolism and the fourth involve lipid signaling (linoleate metabolism). More pathways were altered in pre and post comparisons of stretching, including branched-chain amino acid, tryptophan, tyrosine, and urea cycle, which could indicate loss of lean body mass. Conclusions: These preliminary data show different metabolic changes due to treadmill training and stretching in chronic stroke survivors and suggest that in addition to improved aerobic

Journal of stroke and cerebrovascular diseases, Feb 1, 2014

Background-Insulin resistance is highly prevalent after stroke, contributing to comorbid cardiova... more Background-Insulin resistance is highly prevalent after stroke, contributing to comorbid cardiovascular conditions that are the leading cause of death in the stroke population. This study determined the effects of unilateral resistive training (RT) of both the paretic and nonparetic legs on insulin sensitivity in stroke survivors. Methods-We studied 10 participants (mean age 65 ± 2 years; mean body mass index 27 ± 4 kg/ m 2) with hemiparetic gait after remote (>6 months) ischemic stroke. All subjects underwent 1repetition maximum (1-RM) strength testing, 9 had an oral glucose tolerance test (OGTT), and 7 completed a 2-hour hyperglycemic clamp (with glucose elevation targeted at 98 mg/dL above baseline fasting level) before and after 12 weeks (3×/week) of progressive, high repetition, highintensity RT. Body composition was assessed by dual-energy x-ray absorbtiometry in all participants. Results-Leg press and leg extension 1-RM increased in the paretic leg by 22% (P < .05) and 45% (P < .01), respectively. Fasting insulin decreased 23% (P < .05), with no change in fasting glucose. The 16% reduction in OGTT insulin area under the curve (AUC) across training was not statistically significant (P = .18). There was also no change in glucose AUC. First-phase insulin response during the hyperglycemic clamp (0-10 minutes) decreased 24% (P < .05), and secondphase insulin response (10-120 minutes) decreased 26% (P < .01). Insulin sensitivity increased by 31% after RT according to clamp calculations (P < .05). Conclusions-These findings provide the first preliminary evidence that RT may reduce hyperinsulinemia and improve insulin sensitivity after disabling stroke.

The Journal of Clinical Endocrinology and Metabolism, Dec 1, 1996

Annals of the Rheumatic Diseases, May 30, 2023

Innovation in Aging, Nov 1, 2018

Cells, Dec 10, 2021

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Metabolites, Aug 31, 2020

Angiopoietin-like protein 4 (ANGPTL4) is an adipokine that plays an important role in energy homo... more Angiopoietin-like protein 4 (ANGPTL4) is an adipokine that plays an important role in energy homoeostasis and lipid and lipoprotein metabolism. This study was designed to determine the effect of an exercise plus weight loss intervention on ANGPTL4 expression and its relationship with metabolic health. Thirty-five obese sedentary men (n = 18) and postmenopausal women (n = 17), (X ± SEM, age: 61 ± 1 years, BMI: 31.3 ± 0.7 kg/m 2 , VO 2 max: 21.7 ± 0.9 L/kg/min) completed a 6 month program of 3×/week aerobic exercise and 1×/week dietary instruction to induce weight loss (AEX + WL). Participants underwent vastus lateralis muscle biopsies, a hyperinsulinemic-euglycemic clamp, oral glucose tolerance tests and body composition testing. Basal skeletal muscle ANGPTL4 mRNA was lower in men than women (p < 0.01). Peroxisome proliferator-activated receptor (PPAR) alpha (PPARα) mRNA expression was higher in men than women (p < 0.05). There were no significance changes in serum or skeletal muscle ANGPTL4 (basal or insulin-stimulated) or muscle PPARα mRNA expression after AEX + WL. Muscle mRNA ANGPTL4 is correlated with serum ANGPTL4 (r = 0.41, p < 0.05), body fat (r = 0.64, p < 0.0001), and glucose utilization (r = 0.38, p < 0.05). AEX + WL does not change basal or insulin-stimulated skeletal muscle ANGPTL4 mRNA expression, suggesting other factors contribute to improved insulin sensitivity after the loss of body fat and improved fitness.

Diabetes-metabolism Research and Reviews, May 1, 2013

Background-Reduced density of capillaries in skeletal muscle can limit insulin, glucose, and oxyg... more Background-Reduced density of capillaries in skeletal muscle can limit insulin, glucose, and oxygen supply to the muscle, thereby contributing to worsening metabolism in older adults. The lower skeletal muscle capillarization in impaired glucose tolerance (IGT) may partially be due to circulating angiogenic cell dysfunction. Circulating angiogenic cells maintain the vasculature and promote angiogenesis, but circulating angiogenic cell number and function may be reduced in IGT. The goal of this study was to determine whether the clonogenic potential of circulating angiogenic cells is lower in IGT compared with normal-glucose-tolerant (NGT) controls and is associated with skeletal muscle capillarization. Methods-Glucose tolerance, endothelial cell colony-forming unit (CFU-EC) number, and vastus lateralis capillary density were measured in sedentary, older (62±1 years, mean±SEM) men and women with NGT (n=16) and IGT (n=12). Results-Adults with IGT had 43% lower CFU-EC number (11.4±2.3 versus 20.1±2.0 colonies, p<0.01) and 12% lower capillary density (291±11 versus 330±9 capillaries/mm 2 , p<0.01) compared with those with NGT. In regression analyses, CFU-EC number inversely correlated with 120-min postprandial glucose in all subjects (r=−0.47, p<0.05), and capillary density was directly associated with CFU-EC number (r=0.53, p<0.05). Conclusions-We conclude that the clonogenic potential of circulating angiogenic cells is lower in sedentary older adults with IGT and is associated with lower skeletal muscle capillarization. Low circulating angiogenic cell clonogenic potential in IGT suggests a state of impaired angiogenesis occurring prior to overt type 2 diabetes that may mediate early microvascular changes in the development and progression of IGT to type 2 diabetes. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.

Calcified Tissue International, Mar 11, 2009

Increased inflammation and weight loss are associated with a reduction in bone mineral density (B... more Increased inflammation and weight loss are associated with a reduction in bone mineral density (BMD). Aerobic exercise may minimize the loss of bone and weight loss may contribute to a decrease in cytokines. We tested the hypothesis that aerobic exercise in combination with a weight loss program would decrease circulating concentrations of inflammatory markers, thus mediating changes in BMD. This was a nonrandomized controlled trial. Eighty-six overweight and obese postmenopausal women (50-70 years of age; BMI, 25-40 kg/m 2) participated in a weight loss (WL; n = 40) or weight loss plus walking (WL + AEX; n = 46) program. Outcome measures included BMD and bone mineral content of the femoral neck and lumbar spine measured by dual energy X-ray absorptiometry, interleukin-6, tumor necrosis factor-α, soluble receptors of IL-6, and TNF-α (sTNFR1 and sTNFR2; receptors in a subset of the population), VO 2 max, fat mass, and lean mass. Weight decreased in the WL (p < 0.001) and WL + AEX (p < 0.001) groups. VO 2 max increased (p < 0.001) after WL + AEX. There was a 2% increase in femoral neck BMD in the WL + AEX group (p = 0.001), which was significantly different from the WL group. The change in sTNFR1 was significantly associated with the change in femoral neck BMD (p < 0.05). The change in VO 2 max was an independent predictor of the change in femoral neck BMD. Our findings suggest that the addition of aerobic exercise is recommended to decrease inflammation and increase BMD during weight loss in overweight postmenopausal women.

Physiological Reports, 2016

Skeletal muscle mitochondrial dysfunction may contribute to low aerobic capacity. We previously r... more Skeletal muscle mitochondrial dysfunction may contribute to low aerobic capacity. We previously reported 40% lower aerobic capacity in HIV-infected men compared to noninfected age-matched men. The objective of this study was to compare skeletal muscle mitochondrial enzyme activities in HIVinfected men on antiretroviral therapy (55 AE 1 years of age, n = 10 African American men) with age-matched controls (55 AE 1 years of age, n = 8 Caucasian men), and determine their relationship with aerobic capacity. Activity assays for mitochondrial function including enzymes involved in fatty acid activation and oxidation, and oxidative phosphorylation, were performed in homogenates prepared from vastus lateralis muscle. Hydrogen peroxide (H 2 O 2), cardiolipin, and oxidized cardiolipin were also measured. b-hydroxy acyl-CoA dehydrogenase (b-HAD) (38%) and citrate synthase (77%) activities were significantly lower, and H 2 O 2 (1.4-fold) and oxidized cardiolipin (1.8fold) were significantly higher in HIV-infected men. VO 2 peak (mL/kg FFM/ min) was 33% lower in HIV-infected men and was directly related to b-HAD and citrate synthase activity and inversely related to H 2 O 2 and oxidized cardiolipin. Older HIV-infected men have reduced oxidative enzyme activity and increased oxidative stress compared to age-matched controls. Further research is crucial to determine whether an increase in aerobic capacity by exercise training will be sufficient to restore mitochondrial function in older HIVinfected individuals.

Cells

Zinc α2-glycoprotein (ZAG) has been implicated in fatty acid metabolism and utilization and is lo... more Zinc α2-glycoprotein (ZAG) has been implicated in fatty acid metabolism and utilization and is lower in obese and higher in cachexic adults compared to those of normal weight. Previous studies suggest that ZAG binds to the beta3-adrenergic receptor (β3AR) to influence fatty acid metabolism in adipose tissue by regulating hormone sensitive lipase (HSL). The purpose of this study is to investigate the effects of a six-month weight loss (WL) or aerobic exercise (AEX) intervention on adipose tissue and skeletal muscle ZAG mRNA levels and protein expression, as well as the expression of β3AR, and HSL. Abdominal adipose tissue (AB) and gluteal adipose tissue (Glut) and vastus lateralis muscle biopsies were performed before and after WL (n = 13) or AEX (n = 13). ZAG, HSL, and β3AR expressions were determined by RT-PCR, and ZAG and HSL plasma levels by ELISA. Body weight decreased by 9.69% (p < 0.001) in WL and did not change with AEX. Maximal oxygen consumption (VO2max) increased by 7.1...