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Biomedical subjects

Nathan K LeBrasseur

Publications and source records attributed to Nathan K LeBrasseur.

10 recordsLinked to original sources
PubMed2006

Thiazolidinediones can rapidly activate AMP-activated protein kinase in mammalian tissues.

Thiazolidinediones (TZDs) are insulin-sensitizing agents used in the treatment of type 2 diabetes. A widely held view is that their action is secondary to transcriptional events that occur when TZDs bind to the nuclear receptor PPARgamma in the adipocyte and stimulate adipogenesis. It has been proposed that this increases insulin sensitivity, at least in part, by increasing the expression and release of adiponectin, an adipokine that activates the fuel-sensing enzyme AMP-activated protein kinase (AMPK). In this study, we report that TZDs also acutely activate AMPK in skeletal muscle and other tissues by a mechanism that is likely independent of PPARgamma-regulated gene transcription. Thus incubation of isolated rat EDL muscles in medium containing 5 microM troglitazone for 15 min (too brief to be attributable to transcription) significantly increased pAMPK and pACC. At a concentration of 100 microM, troglitazone maximally increased these parameters and caused twofold increases in 2-deoxy-d-glucose uptake and the oxidation of exogenous [(14)C]palmitate. Time course studies revealed that troglitazone-induced increases in pAMPK and pACC abundance at 15 min were paralleled by an increase in the AMP-to-ATP ratio and that by 60 min all of these parameters had returned to baseline values. Increases in pAMPK and pACC were also observed in skeletal muscle, liver, and adipose tissue in intact rats 15 min after the administration of a single dose of troglitazone (10 mg/kg, ip). Likewise, troglitazone and another TZD, pioglitazone, caused rapid increases in pAMPK and pACC of equal magnitude in Swiss 3T3 fibroblasts with and without sufficient PPARgamma to mediate the expression of target genes. The results indicate that TZDs can act within minutes to activate AMPK in mammalian tissues. They suggest that this effect is associated with a change in cellular energy state and that it is not dependent on PPARgamma-mediated gene transcription.

AMP-Activated Protein Kinases↗
PubMed2006

Muscle impairments and behavioral factors mediate functional limitations and disability following stroke.

BACKGROUND AND PURPOSE: Stroke remains the leading cause of disability in the United States. The purposes of this study were to examine whether quantitative measures of muscle strength and power in the involved lower extremity predict functional limitations and to evaluate the contributions of behavioral factors to mediating disability and quality of life in people who have survived a stroke. SUBJECTS AND METHODS: A cross-sectional study design was used, and measurements of muscle impairment, lower-body function, disability, quality of life, and behavioral factors were obtained for 31 community-dwelling volunteers who had experienced a single ischemic stroke in the past 6 to 24 months. RESULTS: Stepwise regression models including impairment and behavioral measures were strong predictors of function, disability, and quality of life. Involved-extremity muscle strength and power and self-efficacy were independently associated with function, whereas depression and self-efficacy were strong predictors of disability and quality of life. DISCUSSION AND CONCLUSION: The findings warrant future studies to determine whether interventions that address muscle strength and power, depressive symptoms, and low self-efficacy effectively improve function, reduce disability, and enhance quality of life in people who have survived a stroke.

Activities of Daily Living↗
PubMed2005

Oleate prevents palmitate-induced cytotoxic stress in cardiac myocytes.

The cytotoxicity of saturated fatty acids has been implicated in the pathophysiology of cardiovascular disease, though their effects on cardiac myocytes are incompletely understood. We examined the effects of palmitate and the mono-unsaturated fatty acid oleate on neonatal rat ventricular myocyte cell biology. Palmitate (0.5mM) increased oxidative stress, as well as activation of the stress-associated protein kinases (SAPK) p38, Erk1/2, and JNK, following 18h and induced apoptosis in approximately 20% of cells after 24h. Neither antioxidants nor SAPK inhibitors prevented palmitate-induced apoptosis. Low concentrations of oleate (0.1mM) completely inhibited palmitate-induced oxidative stress, SAPK activation, and apoptosis. Increasing mitochondrial uptake of palmitate with l-carnitine decreased apoptosis, while decreasing uptake with the carnitine palmitoyl transferase-1 inhibitor perhexiline nearly doubled palmitate-induced apoptosis. These results support a model for palmitate-induced apoptosis, activation of SAPKs, and protein oxidative stress in myocytes that involves cytosolic accumulation of saturated fatty acids.

Animals↗
PubMed2005

The expression of neuregulin and erbB receptors in human skeletal muscle: effects of progressive resistance training.

The neuregulin/erbB-signaling axis contributes to the development and growth of multiple mammalian tissues including skeletal muscle. In this study, we sought to characterize the native expression of this system in human skeletal muscle and test the hypothesis that a program of progressive resistance training (PRT) would regulate the expression of neuregulin (NRG) and its cognate receptors. Twelve healthy-male subjects underwent 8-weeks of lower-extremity PRT and muscle biopsies were performed at baseline and following 1- and 8-weeks of the intervention. PRT resulted in significant gains in skeletal muscle strength without appreciable changes in fiber size or myosin heavy chain (MHC) composition. At baseline, Western Blot analysis demonstrated expression of erbB2, erbB3 and erbB4 receptors and multiple NRG isoforms. Following 1- and 8-weeks of PRT, no changes erbB2, erbB4 or NRG expression were observed. ErbB3 expression, however, was significantly increased at both time points compared to baseline. Double labeling of muscle cross-sections revealed increased expression of erbB3 following PRT was not exclusive to fibers staining positive for MHC IIa. Thus, erbB2, erbB3, erbB4 and multiple NRG isoforms are natively expressed in human skeletal muscle. Following PRT, a significant increase in erbB3 was observed. The ability to detect basal expression and alterations in response to physiologic stimuli merit further studies examining the role of this system in skeletal muscle.

Adult↗
PubMed2004

High-intensity resistance training improves muscle strength, self-reported function, and disability in long-term stroke survivors.

BACKGROUND AND PURPOSE: To evaluate the efficacy of supervised high-intensity progressive resistance training (PRT) on lower extremity strength, function, and disability in older, long-term stroke survivors. METHODS: Forty-two volunteers aged 50 years and above, 6 months to 6 years after a single mild to moderate stroke, were randomized into either a control group of upper extremity stretching or a PRT group that received a 12-week supervised high-intensity resistance training program consisting of bilateral leg press (LP), unilateral paretic and nonparetic knee extension (KE), ankle dorsiflexion (DF), and plantarflexion (PF) exercises. Functional performance was assessed using the 6-minute walk, stair-climb time, repeated chair-rise time, and habitual and maximal gait velocities. Self-reported changes in function and disability were evaluated using the Late Life Function and Disability Instrument (LLFDI). RESULTS: Single-repetition maximum strength significantly improved in the PRT group for LP (16.2%), paretic KE (31.4%), and nonparetic KE (38.2%) with no change in the control group. Paretic ankle DF (66.7% versus -24.0%), paretic ankle PF (35.5% versus -20.3%), and nonparetic ankle PF (14.7% versus -13.8%) significantly improved in the PRT group compared with the control. The PRT group showed significant improvement in self-reported function and disability with no change in the control. There was no significant difference between groups for any performance-based measure of function. CONCLUSIONS: High-intensity PRT improves both paretic and nonparetic lower extremity strength after stroke, and results in reductions in functional limitations and disability.

Aged↗
PubMed2004

Contraction-mediated mTOR, p70S6k, and ERK1/2 phosphorylation in aged skeletal muscle.

With age, skeletal muscle experiences substantial atrophy and weakness. Although resistance training can increase muscle size and strength, the myogenic response to exercise and the capacity for muscle hypertrophy in older humans and animals is limited. In the present study, we assessed the ability of muscle contractile activity to activate cellular pathways involved in muscle cell growth and myogenesis in adult (Y; 6 mo old) and aged (O; 30 mo old) Fischer 344 x Brown Norway rats. A single bout of rat hindlimb muscle contractile activity was elicited by high-frequency electrical stimulation (HFES) of the sciatic nerve. Plantaris (Pla) and tibialis anterior (TA) muscles were assayed for mammalian target of rapamycin (mTOR), 70-kDa ribosomal protein S6 kinase (p70(S6K)), and extracellular signal-regulated kinase (ERK) 1/2 phosphorylation and total protein either at baseline, immediately after, or 6 h after HFES. mTOR phosphorylation was elevated in Pla (1.3 +/- 0.3-fold, P < 0.05) immediately after HFES and to a lesser extent 6 h after HFES (0.6 +/- 0.1-fold, P < 0.05) in O rats. Post-HFES, p70(S6K) phosphorylation increased 1.2 +/- 0.3-fold in TA (P < 0.05) and remained elevated 6 h later (0.6 +/- 0.2-fold, P < 0.05) in O rats. ERK phosphorylation was lower in O rats immediately after exercise in both TA (11.1 +/- 2.9 vs. 2.1 +/- 0.5-fold, P < 0.05) and Pla (6.5 +/- 1.5 vs. 1.8 +/- 0.5-fold, P < 0.05) and returned to baseline by 6 h in both Y and O rats. Phosphorylation of mTOR, p70(S6K), and ERK1/2 are increased in skeletal muscle after a single bout of in situ muscle contractile activity in aged animals, and the response is less than that observed in adult animals. These observations suggest that the anabolic response to a single bout of contraction is attenuated with aging and may help explain the reduced capacity for hypertrophy in aged animals.

Aging↗
PubMed2003

Differential activation of mTOR signaling by contractile activity in skeletal muscle.

The cellular mechanisms by which contractile activity stimulates skeletal muscle hypertrophy are beginning to be elucidated and appear to include activation of the phosphatidylinositol 3-kinase signaling substrate mammalian target of rapamycin (mTOR). We examined the time course and location of mTOR phosphorylation in response to an acute bout of contractile activity. Rat hindlimb muscle contractile activity was elicited by high-frequency electrical stimulation (HFES) of the sciatic nerve. Plantaris (Pla), tibialis anterior (TA), and soleus (Sol) muscles from stimulated and control limbs were collected immediately or 6 h after stimulation. HFES resulted in mTOR phosphorylation immediately after (3.4 +/- 0.9-fold, P < 0.01) contractile activity in Pla, whereas TA was unchanged compared with controls. mTOR phosphorylation remained elevated in Pla (3.6 +/- 0.6-fold) and increased in TA (4.6 +/- 0.9-fold, P < 0.05) 6 h after HFES. Interestingly, mTOR activation occurred predominantly in fibers expressing type IIa but not type I myosin heavy chain isoform. Furthermore, HFES induced modest ribosomal protein S6 kinase phosphorylation immediately after exercise in Pla (0.4 +/- 0.1-fold, P < 0.05) but not TA and more markedly 6 h after in both Pla and TA (1.4 +/- 0.4-fold vs. 2.4 +/- 0.3-fold, respectively, P < 0.01). Akt/PKB phosphorylation was similar to controls at both time points. These results suggest that mTOR signaling is increased after a single bout of muscle contractile activity. Despite reports that mTOR is activated downstream of Akt/PKB, in this study, HFES induced mTOR signaling independent of Akt/PKB phosphorylation. Fiber type-dependent mTOR phosphorylation may be a molecular basis by which some fiber types are more susceptible to contraction-induced hypertrophy.

Animals↗
PubMed2003

Changes in function and disability after resistance training: does velocity matter?: a pilot study.

OBJECTIVE: To compare the effects of high- and low-velocity resistance training on functional performance and disability outcomes in physically limited older women. DESIGN: A total of 16 wk of high-velocity resistance training or traditional low-velocity resistance training consisting of knee extension and leg press exercises was performed three times per week by 30 women with self-reported disability to compare their effect on functional performance and disability. Tests of dynamic balance, stair-climb time, chair-rise time, and gait velocity were used to assess changes in functional performance. Changes in disability were assessed using the Medical Outcomes Study Short Form. RESULTS: Dynamic balance and stair-climb time improved 8% and 10%, respectively, with training. Self-reported disability, physical functioning, role physical, and mental health improved 11, 9, and 5% with training, respectively. There were no significant differences between high- and low-velocity training groups. CONCLUSIONS: High- and low-velocity training achieved similar improvements in functional performance and disability. Improvements in functional performance and disability were modest compared with robust increases in strength and power. Specific modes of training or behavioral strategies may be necessary to optimize improvements in these outcomes.

Aged↗
PubMed2002

High-velocity resistance training increases skeletal muscle peak power in older women.

OBJECTIVES: Peak power declines more precipitously than strength with advancing age and is a reliable measure of impairment and a strong predictor of functional performance. We tested the hypothesis that a high-velocity resistance-training program (HI) would increase muscle power more than a traditional low-velocity resistance-training program (LO). DESIGN: Randomized controlled trial. SETTING: University-based human physiology laboratory. PARTICIPANTS: Thirty women with self-reported dis-ability (aged 73 + 1, body mass index 30.1 + 1.1 kg/mn). INTERVENTION: We conducted a randomized trial comparing changes in skeletal muscle power and strength after 16 weeks of HI or LO. Training was performed three times per week, and subjects completed three sets (8-10 repetitions) of leg press (LP) and knee extension (KE) exercises at 70% of the one-repetition maximum (IRM). MEASUREMENTS: One-repetition maximum (1 RM) and peak power for KE and LP. RESULTS: LP and KE relative training force and total work were similar between groups (P > .05). However, HI generated significantly higher power during training sessions than LO for LP (3.7-fold greater, P < .001) and KE (2.1-fold greater, P < .001). Although LP and KE 1RM muscle strength increased similarly in both groups asa result of the training (P < .001), LP peak power increased significantly more in HI than in LO (267 W vs 139 W, P < .001). Furthermore, HI resulted in a significantly greater improvement in LP power at 40%, 50%, 60%,70%, 80%, and 90% of the 1 RM than did LO (P <.05). CONCLUSIONS: HI improved 1RM strength similarly and was more effective in improving peak power than was traditional LO in older women. Improvements in lower extremity peak power may exert a greater influence on age-associated reductions in physical functioning than other exercise interventions.

Aged↗