Brian A. Irving

A PGC-1α isoform induced by resistance training regulates skeletal muscle hypertrophy

PGC-1α is a transcriptional coactivator induced by exercise that gives muscle many of the best known adaptations to endurance-type exercise but has no effects on muscle strength or hypertrophy. We have identified a form of PGC-1α (PGC-1α4) that results from alternative promoter usage and splicing of the primary transcript. PGC-1α4 is highly expressed in exercised muscle but does not regulate most known PGC-1α targets such as the mitochondrial OXPHOS genes. Rather, it specifically induces IGF1 and represses myostatin, and expression of PGC-1α4 in vitro and in vivo induces robust skeletal muscle hypertrophy. Importantly, mice with skeletal muscle-specific transgenic expression of PGC-1α4 show increased muscle mass and strength and dramatic resistance to the muscle wasting of cancer cachexia. Expression of PGC-1α4 is preferentially induced in mouse and human muscle during resistance exercise. These studies identify a PGC-1α protein that regulates and coordinates factors involved in skeletal muscle hypertrophy.

Effect of exercise training intensity on abdominal visceral fat and body composition

UNLABELLED The metabolic syndrome is a complex clustering of metabolic defects associated with physical inactivity, abdominal adiposity, and aging. PURPOSE To examine the effects of exercise training intensity on abdominal visceral fat (AVF) and body composition in obese women with the metabolic syndrome. METHODS Twenty-seven middle-aged obese women (mean +/- SD; age = 51 +/- 9 yr and body mass index = 34 +/- 6 kg x m(-2)) with the metabolic syndrome completed one of three 16-wk aerobic exercise interventions: (i) no-exercise training (Control): seven participants maintained their existing levels of physical activity; (ii) low-intensity exercise training (LIET): 11 participants exercised 5 d x wk(-1) at an intensity < or = lactate threshold (LT); and (iii) high-intensity exercise training (HIET): nine participants exercised 3 d x wk(-1) at an intensity > LT and 2 d x wk(-1) < or = LT. Exercise time was adjusted to maintain caloric expenditure (400 kcal per session). Single-slice computed tomography scans obtained at the L4-L5 disc space and midthigh were used to determine abdominal fat and thigh muscle cross-sectional areas. Percent body fat was assessed by air displacement plethysmography. RESULTS HIET significantly reduced total abdominal fat (P < 0.001), abdominal subcutaneous fat (P = 0.034), and AVF (P = 0.010). There were no significant changes observed in any of these parameters within the Control or the LIET conditions. CONCLUSIONS The present data indicate that body composition changes are affected by the intensity of exercise training with HIET more effectively for reducing total abdominal fat, subcutaneous abdominal fat, and AVF in obese women with the metabolic syndrome.

Asian Indians Have Enhanced Skeletal Muscle Mitochondrial Capacity to Produce ATP in Association with Severe Insulin-Resistance

OBJECTIVE— Type 2 diabetes has become a global epidemic, and Asian Indians have a higher susceptibility to diabetes than Europeans. We investigated whether Indians had any metabolic differences compared with Northern European Americans that may render them more susceptible to diabetes. RESEARCH DESIGN AND METHODS— We studied 13 diabetic Indians, 13 nondiabetic Indians, and 13 nondiabetic Northern European Americans who were matched for age, BMI, and sex. The primary comparisons were insulin sensitivity by hyperinsulinemic-euglycemic clamp and skeletal muscle mitochondrial capacity for oxidative phosphorylation (OXPHOS) by measuring mitochondrial DNA copy number (mtDNA), OXPHOS gene transcripts, citrate synthase activity, and maximal mitochondrial ATP production rate (MAPR). Other factors that may cause insulin resistance were also measured. RESULTS— The glucose infusion rates required to maintain identical glucose levels during the similar insulin infusion rates were substantially lower in diabetic Indians than in the nondiabetic participants (P < 0.001), and they were lower in nondiabetic Indians than in nondiabetic Northern European Americans (P < 0.002). mtDNA (P < 0.02), OXPHOS gene transcripts (P < 0.01), citrate synthase, and MAPR (P < 0.03) were higher in Indians irrespective of their diabetic status. Intramuscular triglyceride, C-reactive protein, interleukin-6, and tumor necrosis factor-α concentrations were higher, whereas adiponectin concentrations were lower in diabetic Indians. CONCLUSIONS— Despite being more insulin resistant, diabetic Indians had similar muscle OXPHOS capacity as nondiabetic Indians, demonstrating that diabetes per se does not cause mitochondrial dysfunction. Indians irrespective of their diabetic status had higher OXPHOS capacity than Northern European Americans, although Indians were substantially more insulin resistant, indicating a dissociation between mitochondrial dysfunction and insulin resistance.

Age, Obesity, and Sex Effects on Insulin Sensitivity and Skeletal Muscle Mitochondrial Function

OBJECTIVE Reductions in insulin sensitivity in conjunction with muscle mitochondrial dysfunction have been reported to occur in many conditions including aging. The objective was to determine whether insulin resistance and mitochondrial dysfunction are directly related to chronological age or are related to age-related changes in body composition. RESEARCH DESIGN AND METHODS Twelve young lean, 12 young obese, 12 elderly lean, and 12 elderly obese sedentary adults were studied. Insulin sensitivity was measured by a hyperinsulinemic-euglycemic clamp, and skeletal muscle mitochondrial ATP production rates (MAPRs) were measured in freshly isolated mitochondria obtained from vastus lateralis biopsy samples using the luciferase reaction. RESULTS Obese participants, independent of age, had reduced insulin sensitivity based on lower rates of glucose infusion during a hyperinsulinemic-euglycemic clamp. In contrast, age had no independent effect on insulin sensitivity. However, the elderly participants had lower muscle MAPRs than the young participants, independent of obesity. Elderly participants also had higher levels inflammatory cytokines and total adiponectin. In addition, higher muscle MAPRs were also noted in men than in women, whereas glucose infusion rates were higher in women. CONCLUSIONS The results demonstrate that age-related reductions in insulin sensitivity are likely due to an age-related increase in adiposity rather than a consequence of advanced chronological age. The results also indicate that an age-related decrease in muscle mitochondrial function is neither related to adiposity nor insulin sensitivity. Of interest, a higher mitochondrial ATP production capacity was noted in the men, whereas the women were more insulin sensitive, demonstrating further dissociation between insulin sensitivity and muscle mitochondrial function.

Preoperative prediction of type 2 diabetes remission after Roux-en-Y gastric bypass surgery: a retrospective cohort study

BACKGROUND About 60% of patients with type 2 diabetes achieve remission after Roux-en-Y gastric bypass (RYGB) surgery. No accurate method is available to preoperatively predict the probability of remission. Our goal was to develop a way to predict probability of diabetes remission after RYGB surgery on the basis of preoperative clinical criteria. METHODS In a retrospective cohort study, we identified individuals with type 2 diabetes for whom electronic medical records were available from a primary cohort of 2300 patients who underwent RYGB surgery at the Geisinger Health System (Danville, PA, USA) between Jan 1, 2004, and Feb 15, 2011. Partial and complete remission were defined according to the American Diabetes Association criteria. We examined 259 clinical variables for our algorithm and used multiple logistic regression models to identify independent predictors of early remission (beginning within first 2 months after surgery and lasting at least 12 months) or late remission (beginning more than 2 months after surgery and lasting at least 12 months). We assessed a final Cox regression model with a consistent subset of variables that predicted remission, and used the resulting hazard ratios (HRs) to guide creation of a weighting system to produce a score (DiaRem) to predict probability of diabetes remission within 5 years. We assessed the validity of the DiaRem score with data from two additional cohorts. FINDINGS Electronic medical records were available for 690 patients in the primary cohort, of whom 463 (63%) had achieved partial or complete remission. Four preoperative clinical variables were included in the final Cox regression model: insulin use, age, HbA1c concentration, and type of antidiabetic drugs. We developed a DiaRem score that ranges from 0 to 22, with the greatest weight given to insulin use before surgery (adding ten to the score; HR 5·90, 95% CI 4·41–7·90; p<0·0001). Kaplan-Meier analysis showed that 88% (95% CI 83–92%) of patients who scored 0–2, 64% (58–71%) of those who scored 3–7, 23% (13–33%) of those who scored 8–12, 11% (6–16%) of those who scored 13–17, and 2% (0–5%) of those who scored 18–22 achieved early remission (partial or complete). As in the primary cohort, the proportion of patients achieving remission in the replication cohorts was highest for the lowest scores, and lowest for the highest scores. INTERPRETATION The DiaRem score is a novel preoperative method to predict the probability of remission of type 2 diabetes after RYGB surgery. FUNDING Geisinger Health System and the US National Institutes of Health.

NIH ImageJ and Slice‐O‐Matic Computed Tomography Imaging Software to Quantify Soft Tissue

Objective: To compare reliability and limits of agreement of soft tissue cross‐sectional areas obtained using Slice‐O‐Matic and NIH ImageJ medical imaging software packages.

Unique cellular and mitochondrial defects mediate FK506-induced islet β-cell dysfunction

Objective. To determine biological mechanisms involved in posttransplantation diabetes mellitus caused by the immunosuppressant tacrolimus (FK506). Methods. INS-1 cells and isolated rat islets were incubated with vehicle or FK506 and harvested at 24-hr intervals. Cells were assessed for viability, apoptosis, proliferation, cell insulin secretion, and content. Gene expression studies by microarray analysis, quantitative polymerase chain reaction, and motifADE analysis of the microarray data identified potential FK506-mediated pathways and regulatory motifs. Mitochondrial functions, including cell respiration, mitochondrial content, and bioenergetics were assessed. Results. Cell replication, viability, insulin secretion, oxygen consumption, and mitochondrial content were decreased (P<0.05) 1.2-, 1.27-, 1.77-, 1.32-, and 1.43-fold, respectively, after 48-hr FK506 treatment. Differences increased with time. FK506 (50 ng/mL) and cyclosporine A (800 ng/mL) had comparable effects. FK506 significantly decreased mitochondrial content and mitochondrial bioenergetics and showed a trend toward decreased oxygen consumption in isolated islets. Cell apoptosis and proliferation, mitochondrial DNA copy number, and ATP:ADP ratios were not significantly affected. Pathway analysis of microarray data showed FK506 modification of pathways involving ATP metabolism, membrane trafficking, and cytoskeleton remodeling. PGC1-&agr; mRNA was down-regulated by FK506. MotifADE identified nuclear factor of activated T-cells, an important mediator of &bgr;-cell survival and function, as a potential factor mediating both up- and down-regulation of gene expression. Conclusions. At pharmacologically relevant concentrations, FK506 decreases insulin secretion and reduces mitochondrial density and function without changing apoptosis rates, suggesting that posttransplantation diabetes induced by FK506 may be mediated by its effects on mitochondrial function.

Effect of testosterone on insulin stimulated IRS1 Ser phosphorylation in primary rat myotubes--a potential model for PCOS-related insulin resistance.

Background Polycystic ovary syndrome (PCOS) is characterized by a hyperandrogenic state and frequently develops skeletal muscle insulin resistance. We determined whether testosterone adversely affects insulin action by increasing serine phosphorylation of IRS-1636/639 in differentiated rat skeletal muscle myotubes. The phosphorylation of Akt, mTOR, and S6K, downstream targets of the PI3-kinase-IRS-1 complex were also studied. Methods Primary differentiated rat skeletal muscle myotubes were subjected to insulin for 30 min after 16-hour pre-exposure to either low (20 ng/ml) or high (200 ng/ml) doses of testosterone. Protein phosphorylation of IRS-1 Ser636/639, Akt Ser473, mTOR-Ser2448, and S6K-Thr389 were measured by Western blot with signal intensity measured by immunofluorescence. Results Cells exposed to 100 nM of insulin had increased IRS-1 Ser636/639 and Akt Ser473 phosphorylation. Cells pre-exposed to low-dose testosterone had significantly increased insulin-induced mTOR-Ser2448 and S6K-Thr389 phosphorylation (p<0.05), and further increased insulin-induced IRS-1 Ser636/639 phosphorylation (p = 0.042) compared to control cells. High-dose testosterone pre-exposure attenuated the insulin-induced mTOR-Ser2448 and S6K-Thr389 phosphorylation. Conclusions The data demonstrated an interaction between testosterone and insulin on phosphorylation of intracellular signaling proteins, and suggests a link between a hyperandrogenic, hyperinsulinemic environment and the development of insulin resistance involving serine phosphorylation of IRS-1 Ser636/639. These results may guide further investigations of potential mechanisms of PCOS-related insulin resistance.

Defects in mitochondrial efficiency and H2O2 emissions in obese women are restored to a lean phenotype with aerobic exercise training

The notion that mitochondria contribute to obesity-induced insulin resistance is highly debated. Therefore, we determined whether obese (BMI 33 kg/m2), insulin-resistant women with polycystic ovary syndrome had aberrant skeletal muscle mitochondrial physiology compared with lean, insulin-sensitive women (BMI 23 kg/m2). Maximal whole-body and mitochondrial oxygen consumption were not different between obese and lean women. However, obese women exhibited lower mitochondrial coupling and phosphorylation efficiency and elevated mitochondrial H2O2 (mtH2O2) emissions compared with lean women. We further evaluated the impact of 12 weeks of aerobic exercise on obesity-related impairments in insulin sensitivity and mitochondrial energetics in the fasted state and after a high-fat mixed meal. Exercise training reversed obesity-related mitochondrial derangements as evidenced by enhanced mitochondrial bioenergetics efficiency and decreased mtH2O2 production. A concomitant increase in catalase antioxidant activity and decreased DNA oxidative damage indicate improved cellular redox status and a potential mechanism contributing to improved insulin sensitivity. mtH2O2 emissions were refractory to a high-fat meal at baseline, but after exercise, mtH2O2 emissions increased after the meal, which resembles previous findings in lean individuals. We demonstrate that obese women exhibit impaired mitochondrial bioenergetics in the form of decreased efficiency and impaired mtH2O2 emissions, while exercise effectively restores mitochondrial physiology toward that of lean, insulin-sensitive individuals.

Nine days of intensive exercise training improves mitochondrial function but not insulin action in adult offspring of mothers with type 2 diabetes.

CONTEXT A close association between insulin resistance and reduced skeletal muscle oxidative capacity has been reported in adult offspring of people with type 2 diabetes (T2D), prompting a hypothesis that insulin resistance may result from mitochondrial dysfunction or vice versa. OBJECTIVE We determined whether 9 d of intensive exercise training ameliorates the mitochondrial dysfunction and insulin resistance in offspring of T2D. METHODS We compared the response to 9 d of intensive exercise training in eight (seven females, one male) healthy adult offspring of mothers with T2D with eight (six females, two males) nondiabetic controls. Skeletal muscle mitochondrial ATP production was assessed using a luciferase-based assay, and insulin sensitivity was measured using hyperinsulinemic-euglycemic clamps. RESULTS Short-term intensive training increased skeletal muscle mitochondrial ATP production and citrate synthase activity similarly in both groups (P < 0.01). In contrast, whereas short-term intensive training reduced the fasting glucose (~5%, P = 0.035) and insulin levels (~40%, P = 0.011) as well as increased the glucose infusion rate during the hyperinsulinemic-euglycemic clamp (~50%, P = 0.028) among controls, no changes in these parameters were observed among offspring except for an increase in fasting glucose (~7%, P = 0.004). CONCLUSION A short-term intensive exercise training program was equally effective at increasing skeletal muscle oxidative capacity in nondiabetic people and in the offspring of mothers with diabetes. In contrast, the exercise improved insulin sensitivity only in nondiabetic people but not in the offspring of T2D mothers, revealing dissociation between improvements in skeletal muscle mitochondrial function and insulin sensitivity. The exercise effect on mitochondrial function and insulin sensitivity seems to be mediated by different regulatory pathways.