Medical Library

Book review / Critique de livre.

Shephard RJ.

The role of protein-mediated transport in regulating mitochondrial long-chain fatty acid oxidation.

This thesis is an investigation of the role of fatty acid translocase (FAT/CD36), plasma membrane associated fatty acid binding protein (FABPpm), and carnitine palmitoyltransferase I (CPTI) in transporting long-chain fatty acids (LCFAs) across mitochondrial membranes. Maximal CPTI activity, as well as the sensitivity of CPTI for its substrate palmitoyl-CoA (P-CoA) and its inhibitor malonyl-CoA (M-CoA), were measured in mitochondria isolated from human vastus lateralis muscles at rest and following muscle contraction. Exercise did not alter maximal CPTI activity or the sensitivity of CPTI for P-CoA. In contrast, exercise progressively attenuated the ability of M-CoA to inhibit CPTI activity. Mitochondrial FAT/CD36 protein content was also measured at rest, during, and following 2 h of cycling at ~60% maximal oxygen uptake. Exercise progressively increased the content of mitochondrial FAT/CD36 (+59%), which was significantly (p < 0.05) correlated with palmitate oxidation during exercise (r = 0.52), while palmitate oxidation was inhibited ~80% by the administration of a specific FAT/CD36 inhibitor. These data suggest that alterations in CPTI M-CoA sensitivity and increases in mitochondrial FAT/CD36 coordinate exercise-induced increases in fatty acid oxidation. FABPpm, another plasma membrane transport protein, has identical amino acid sequence to mitochondrial aspartate aminotransferase (mAspAT). Since FABPpm contributes to plasma membrane fatty acid transport, the role of FABPpm with respect to mitochondrial LCFA transport was investigated. However, unlike FAT/CD36, muscle contraction did not induce an increase in mitochondrial FABPpm protein in rat or human skeletal muscle. In addition, electrotransfecting FABPpm cDNA into rat skeletal muscle upregulated this protein in mitochondria by 80% without altering mitochondrial palmitate oxidation. In contrast, electrotransfection increased mAspAT activity by 90%, and this was correlated (r = 0.75; p < 0.01) with FABPpm protein. These data suggest that FABPpm does not contribute to the regulation of mitochondrial LCFA transport. Previously, it has been suggested that mitochondria from obese individuals contain an inherent dysfunction to oxidize LCFAs. In age-matched lean (BMI = 23.3 +/- 0.7 kg.m-2) and obese (BMI = 37.6 +/- 2.2 kg.m-2) individuals, isolated mitochondrial palmitate oxidation was not altered. In addition, mitochondrial FAT/CD36 content was not different in lean and obese individuals. In contrast, citrate synthase and &beta;-hydroxyacyl-CoA dehydrogenase, common markers of total mitochondrial content, were decreased with obesity. Therefore, the decrease in mitochondrial content appeared to account for the observed reductions in whole-muscle LCFA oxidation.

Holloway GP.

Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON N1G 2W1 (e-mail: ghollowa@uoguelph.ca).

Determinants of VO2 max decline with aging: an integrated perspective.

Aging is associated with a progressive decline in the capacity for physical activity. Central to this decline is a reduction in the maximal rate of oxygen utilization, or VO2 max. This critical perspective examines the roles played by the factors that determine the rate of muscle oxygen delivery versus those that determine the utilization of oxygen by muscle as a means of probing the reasons for VO2 max decline with aging. Reductions in muscle oxygen delivery, principally due to reduced cardiac output and perhaps also a maldistribution of cardiac output, appear to play the dominant role up until late middle age. On the other hand, there is a decline in skeletal muscle oxidative capacity with aging, due in part to mitochondrial dysfunction, which appears to play a particularly important role in extreme old age (senescence) where skeletal muscle VO2 max is observed to decline by approximately 50% even under conditions of similar oxygen delivery as young adult muscle. It is noteworthy that at least the structural aspects of the capillary bed do not appear to be reduced in a manner that would compromise the capacity for muscle oxygen diffusion even in senescence.

Betik AC, Hepple RT.

Faculty of Kinesiology, University of Calgary, 2500 University Dr. NW, Calgary, AB T2N 1N4.

Muscling in on microarrays.

Adaptations that are the result of exercise require a multitude of changes at the level of gene expression. The mechanisms involved in regulating these changes are many, and can occur at various points in the pathways that affect gene expression. The completion of the human genome sequence, along with the genomes of related species, has provided an enormous amount of information to help dissect and understand these pathways. High-throughput methods, such as DNA microarrays, were the first on the scene to take advantage of this wealth of information. A new generation of microarrays has now taken the next step in revealing the mechanisms controlling gene expression. Analysis of the regulation of gene expression can now be profiled in a high-throughput fashion. However, the application of this technology has yet to be fully realized in the exercise physiology community. This review will highlight some of the latest advances in microarrays and briefly discuss some potential applications to the field of exercise physiology.

Virtanen C, Takahashi M.

Microarray Centre, University Health Network, MaRS Centre, Toronto Discovery Tower, 101 College St., Toronto, ON M5G 1L7, Canada.

Are functional foods redefining nutritional requirements?

Functional foods are increasing in popularity owing to their ability to confer health and physiological benefits. Nevertheless, the notion that functional foods improve health when providing nutrients at levels above and beyond existing recommended intakes is inconsistent with the definition of requirement. This disparity highlights the need for an alternative definition of nutrient requirement. The present objective is to examine distinctions between optimization of health, as defined by what we currently deem as required intakes, versus adding physiological benefit using bioactive agents found in functional foods. Presently, requirement is defined as the lowest amount of intake of a nutrient that will maintain a defined level of nourishment for a specific indicator of adequacy. In contrast, functional foods are described as ingredients that are not necessary for body function, yet provide added physiological benefit that confer better overall health. Plant sterols are one example of such an ingredient. Plant sterols lower plasma cholesterol concentrations, and may thus be considered essential nutrients in physiological situations where circulating cholesterol concentrations are high. Similarly, intakes of omega-3 fats beyond existing requirement may confer additional health benefits such as hypolipidemic and anti-diabetic effects. These examples underscore the inconsistencies between what is defined as a nutrient requirement versus what is identified as a health benefit of a functional food. Such discrepancies emphasize the need for a more all-encompassing definition of a nutrient requirement; that is, one that moves beyond the prevention of overt deficiency to encompass improved health and disease risk reduction.

Jones PJ, Varady KA.

Richardson Centre for Functional Foods and Nutraceuticals, University of Manitoba, 196 Innovation Dr., Winnipeg, MB R3T 6C5.

Influence of exercise intensity on pulmonary oxygen uptake kinetics at the onset of exercise and recovery in male adolescents.

The dynamics of the pulmonary oxygen uptake (VO2) responses to square-wave changes in work rate can provide insight into bioenergetic processes sustaining and limiting exercise performance. The dynamic responses at the onset of exercise and during recovery have been investigated systematically and are well characterized at all intensities in adults; however, they have not been investigated completely in adolescents. We investigated whether adolescents display a slow component in their VO2 on- and off-kinetic responses to heavy- and very heavy-intensity exercise, as demonstrated in adults. Healthy African American male adolescents (n = 9, 14-17 years old) performed square-wave transitions on a cycle ergometer (from and to a baseline work rate of 20 W) to work rates of moderate (M), heavy (H), and very heavy (VH) intensity. In all subjects, the VO2 on-kinetics were best described with a single exponential at moderate intensity (&tau;1, on = 36 +/- 11 s) and a double exponential at heavy (&tau;1, on = 29 +/- 9 s; &tau;2, on = 197 +/- 92 s) and very heavy (&tau;1, on = 36 +/- 9 s; &tau;2, on = 302 +/- 14 s) intensities. In contrast, the VO2 off-kinetics were best described with a single exponential at moderate (&tau;1, off = 48 +/- 9 s) and heavy (&tau;1, off = 53 +/- 7 s) intensities and a double exponential at very heavy (&tau;1, off = 51 +/- 3 s; &tau;2, off = 471 +/- 54 s) intensity. In summary, adolescents consistently displayed a slow component during heavy exercise (on- but not off- transition) and very heavy exercise (on- and off-transitions). Although the overall response dynamics in adolescents were similar to those previously observed in adults, their specific characterizations were different, particularly the lack of symmetry between the on- and off-responses.

Lai N, Nasca MM, Silva MA, Silva FT, Whipp BJ, Cabrera ME.

Department of Biomedical Engineering, Case Western University, Cleveland, Ohio, USA.

Use of parenteral nutrition in patients with advanced cancer.

The purpose of this study is to describe patient-related variables in a cohort of advanced cancer patients (ACPs) enrolled in a home parenteral nutrition (HPN) program. This study reviewed the cohort of ACPs enrolled in the Northern Alberta Home Total Parenteral Nutrition Program (NAHTPNP). Thirty-eight ACPs received HPN during the study period, 24% of all patients admitted for PN. Of these, 27 (71%) were female. Mean age was 48.76 y (SD 13.8 y). Bowel obstruction was the most common indication for initiating HPN (84%, 32) and ovarian cancer was the most common malignancy (34%, 13). Patients who began HPN with a Karnofsky performance status (KPS) of greater than 50 (median of 70) were found to have a longer duration of life (median: 6 months) compared with patients who began HPN with a KPS of 50 or below (median = 50; median 3 months; p = 0.01; two-tailed). There was no difference in survival between malignancy type (p = NS). Advanced cancer is the fastest growing indication for enrollment in the HPN program. ACP demonstrated a 3% average annual increase proportionate to all indications for HPN starts, accounting for 7%-48% of HPN starts from 1999-2006. HPN is an increasingly used therapy for patients with advanced cancer, most commonly for intestinal failure in the setting of bowel obstruction. Initiation of HPN at a higher KPS was associated with a longer duration of life. Further studies are needed to validate the use of TPN in end-stage cancer patients.

Soo I, Gramlich L.

Faculty of Medicine, University of Alberta, Edmonton, AB T6G 2E1.

A chronic increase in physical activity inhibits fed-state mTOR/S6K1 signaling and reduces IRS-1 serine phosphorylation in rat skeletal muscle.

A chronic increase in physical activity and (or) endurance training can improve insulin sensitivity in insulin-resistant skeletal muscle. Cellular mechanisms responsible for the development of insulin resistance are unclear, though one proposed mechanism is that nutrient overload chronically increases available energy, over-activating the mammalian target of rapamycin (mTOR) and ribosomal S6 kinase 1 (S6K1) signaling pathway leading to increased phosphorylation of serine residues on insulin receptor substrate-1 (IRS-1). The objective of this study was to determine if increased physical activity would inhibit mTOR/S6K1 signaling and reduce IRS-1 serine phosphorylation in rat skeletal muscle. Soleus muscle was collected from fed male Sprague-Dawley sedentary rats (Inactive) and rats with free access to running wheels for 9 weeks (Active). Immunoblotting methods were used to measure phosphorylation status of mTOR, S6K1, IRS-1, and PKB/Akt (protein kinase B/AKT), and total abundance of proteins associated with the mTOR pathway. Muscle citrate synthase activity and plasma insulin and glucose concentrations were measured. Phosphorylation of mTOR (Ser2448), S6K1 (Thr389), and IRS-1 (Ser636-639) was reduced in Active rats (p < 0.05). Total protein abundance of mTOR, S6K1, IRS-1, 4E-BP1, eEF2, PKB/Akt and AMPK&alpha;, and phosphorylation of PKB/Akt were unaffected (p > 0.05). Total SKAR protein, a downstream target of S6K1, and citrate synthase activity increased in Active rats (p < 0.05), though plasma insulin and glucose levels were unchanged (p > 0.05). Reduced mTOR/S6K1 signaling during chronic increases in physical activity may play an important regulatory role in the serine phosphorylation of IRS-1, which should be examined as a potential mechanism for attenuation of insulin resistance associated with increased IRS-1 serine phosphorylation.

Glynn EL, Lujan HL, Kramer VJ, Drummond MJ, Dicarlo SE, Rasmussen BB.

Division of Rehabilitation Sciences, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555-1144, USA.

Increase in depression symptoms with weight loss: association with glucose homeostasis and thyroid function.

The purpose of this study was to assess the potential impact of weight loss up to a state of plateau on symptoms of depression. Eleven obese men (mean body mass index (BMI) = 33.4 kg.m-2, mean age = 38 y) participated in this repeated-measures, within-subjects, clinical intervention. They were subjected to a weight-loss program that consisted of a supervised diet and exercise clinical intervention. The phases investigated were (i) baseline; (ii) after 5 +/- 1 kg loss of body mass (phase 1); (iii) after 10 +/- 1 kg weight loss (phase 2); and (iv) at resistance to further weight loss (plateau). At each phase of the weight-reducing program, glucose homeostasis markers were determined using an oral glucose tolerance test (OGTT). Serum thyroid-stimulating hormone (TSH), total triiodothyronine (T3), and free thyroxine (fT4) concentrations were also measured and the Beck Depression Inventory (BDI) was administered. The weight loss plateau occurred after 7.4 +/- 1.9 months of intervention and corresponded to a loss of 11.2% of initial body weight (93.9% of which was from fat stores). This amount of weight loss induced a significant decrease in resting metabolic rate (RMR) (p < 0.05) and a significant increase in desire to eat (p < 0.05) and in depression symptoms (p < 0.01) compared with baseline. Intriguingly, the glucose area below fasting values (GABF) at plateau was significantly higher as compared with other phases of the program (p < 0.01). We found a strong negative correlation (r = -0.77, p < 0.01) between the change in glucose concentrations at 180 min of the OGTT and the change in BDI scores between plateau and baseline values. Similarly, highly significant relationships were found between the change in T3 or fT4 concentrations and the change in BDI scores (r = -0.71 and r = -0.68, respectively; p < 0.01). Weight loss until plateauing is associated with a trend toward hypoglycemia at the end of the oral glucose challenge and with a decrease in T3 and fT4 levels. These physiological changes are shown to be highly linked with the increase in depression symptoms observed at plateau. Taken together, these data emphasize the relevance of caution and reasonable objectives when prescribing a weight reduction program to obese individuals.

Chaput JP, Arguin H, Gagnon C, Tremblay A.

Division of Kinesiology, Department of Social and Preventive Medicine, Faculty of Medicine, Laval University, Quebec City, QC G1K 7P4.

AMPK inactivation in mononuclear cells: a potential intracellular mechanism for exercise-induced immunosuppression.

There is much evidence that prolonged intense exercise suppresses the immune system. However, the intracellular biochemical mechanisms linking exercise and immunosuppression remain obscure. The purpose of this study was to investigate the hypothesis that exercise-induced inactivation of 5&prime;AMP-activated protein kinase (AMPK) disrupts individual immune cell function, and thus may be linked to exercise-induced immunosuppression. To confirm AMPK\’s role in immune cells, AMPK activity was assessed in cultured monocytic Mono Mac 6 (MM6) cells. The effects of single bouts of intense exercise (45 min cycling; 70% VO2 max) on several immune parameters including mononuclear cell AMPK phosphorylation were investigated in 10 male volunteers. In vitro, the mitochondrial ATP synthase inhibitor oligomycin brought about transient decreases in cellular [ATP] (0.41 +/- 0.04 pmol/cell to 0.31 +/- 0.02 pmol/cell), and activation of AMPK&alpha;1 (170.7% +/- 31.2% basal) and the glycolytic enzyme inducible phosphofructokinase 2 (iPFK-2) (225.0% +/- 46.1% basal), with the latter effects coinciding with recovery from ATP depletion. In contrast, exercise-induced transient (~1 h) decreases in AMPK&alpha;1 phosphorylation (64.4% +/- 17.6% basal). This AMPK inactivation coincided with comparable transient decreases in other immune parameters (salivary IgA levels, serum cytokine levels, monocyte CD36 expression). Although the brief exercise bout employed here is not sufficient to cause full-fledged immunosuppression, exercise-induced transient decreases in mononuclear cell AMPK activation (as seen in this study) may cause energy depletion within individual immune cells, and therefore have an impact upon their ability to carry out their functions. Thus, we suggest that prolonged, repeated, high-intensity exercise that leads to clinically relevant immunosuppression may do so via AMPK inactivation within immune cells.

Moir H, Butcher L, Jones KP, Hughes MG, Neale H, Jia H, Al-Ismaily Z, Webb R.

Cardiff School of Health Sciences, Centre for Biomedical Sciences, University of Wales Institute Cardiff, Cardiff, Wales CF5 2YB, UK.