Characteristics of skeletal muscle mitochondrial biogenesis induced by moderate-intensity exercise and weight loss in obesity.

There are fewer mitochondria and a reduced oxidative capacity in skeletal muscle in obesity. Moderate-intensity physical activity combined with weight loss increase oxidative enzyme activity in obese sedentary adults; however, this adaptation occurs without a significant increase in mitochondrial DNA (mtDNA), which is unlike the classic pattern of mitochondrial biogenesis induced by vigorous activity. The objective of this study was to examine the hypothesis that the mitochondrial adaptation to moderate-intensity exercise and weight loss in obesity induces increased mitochondrial cristae despite a lack of mtDNA proliferation. Content of cardiolipin and mtDNA and enzymatic activities of the electron transport chain (ETC) and tricarboxylic acid cycle were measured in biopsy samples of vastus lateralis muscle obtained from sedentary obese men and women before and following a 4-mo walking intervention combined with weight loss. Cardiolipin increased by 60% from 47 +/- 4 to 74 +/- 8 microg/mU CK (P < 0.01), but skeletal muscle mtDNA content did not change significantly (1,901 +/- 363 to 2,169 +/- 317 Rc, where Rc is relative copy number of mtDNA per diploid nuclear genome). Enzyme activity of the ETC increased (P < 0.01); that for rotenone-sensitive NADH-oxidase (96 +/- 1%) increased more than for ubiquinol-oxidase (48 +/- 6%). Activities for citrate synthase and succinate dehydrogenase increased by 29 +/- 9% and 40 +/- 6%, respectively. In conclusion, moderate-intensity physical activity combined with weight loss induces skeletal muscle mitochondrial biogenesis in previously sedentary obese men and women, but this response occurs without mtDNA proliferation and may be characterized by an increase in mitochondrial cristae.     

A discordance in rosiglitazone mediated insulin sensitization and skeletal muscle mitochondrial content/activity in Type 2 diabetes mellitus

Skeletal muscle mitochondrial dysfunction is hypothesized to contribute to the pathophysiology of insulin resistance and Type 2 diabetes. Whether thiazolidinedione therapy enhances skeletal muscle mitochondrial function as a component of its insulin-sensitizing effect is unknown. To test this, we evaluated skeletal muscle mitochondria and exercise capacity in Type 2 diabetic subjects with otherwise normal cardiopulmonary function in response to rosiglitazone therapy. Twenty-three subjects were treated for 12 wk and underwent pre- and posttherapy metabolic stress testing and skeletal muscle biopsies. Rosiglitazone significantly ameliorated fasting glucose, insulin, and free fatty acid levels but did not augment the subjects' maximal oxygen consumption (Vo(2max)) or their skeletal muscle mitochondrial copy number. The baseline Vo(2max) correlated strongly with muscle mitochondrial copy number (r = 0.56, P = 0.018, n = 17) and inversely with the duration of diabetes (r = -0.67, P = 0.004, n = 23). Despite the global lack of effect of rosiglitazone-mediated insulin sensitization on skeletal muscle mitochondria, subjects with the most preserved functional capacity demonstrated some plasticity in their mitochondria biology as evidenced by an upregulation of electron transfer chain proteins and in citrate synthase activity. This study demonstrates that the augmentation of skeletal muscle mitochondrial electron transfer chain content and/or bioenergetics is not a prerequisite for rosiglitazone-mediated improved insulin sensitivity. Moreover, in diabetic subjects, Vo(2max) reflects the duration of diabetes and skeletal muscle mitochondrial content. It remains to be determined whether longer-term insulin sensitization therapy with rosiglitazone will augment skeletal muscle mitochondrial bioenergetics in those diabetic subjects with relatively preserved basal aerobic capacity.     

Exercise and diet enhance fat oxidation and reduce insulin resistance in older obese adults.

Older, obese, and sedentary individuals are at high risk of developing diabetes and cardiovascular disease. Exercise training improves metabolic anomalies associated with such diseases, but the effects of caloric restriction in addition to exercise in such a high-risk group are not known. Changes in body composition and metabolism during a lifestyle intervention were investigated in 23 older, obese men and women (aged 66 +/- 1 yr, body mass index 33.2 +/- 1.4 kg/m(2)) with impaired glucose tolerance. All volunteers undertook 12 wk of aerobic exercise training [5 days/wk for 60 min at 75% maximal oxygen consumption (Vo(2max))] with either normal caloric intake (eucaloric group, 1,901 +/- 277 kcal/day, n = 12) or a reduced-calorie diet (hypocaloric group, 1,307 +/- 70 kcal/day, n = 11), as dictated by nutritional counseling. Body composition (decreased fat mass; maintained fat-free mass), aerobic fitness (Vo(2max)), leptinemia, insulin sensitivity, and intramyocellular lipid accumulation (IMCL) in skeletal muscle improved in both groups (P < 0.05). Improvements in body composition, leptin, and basal fat oxidation were greater in the hypocaloric group. Following the intervention, there was a correlation between the increase in basal fat oxidation and the decrease in IMCL (r = -0.53, P = 0.04). In addition, basal fat oxidation was associated with circulating leptin after (r = 0.65, P = 0.0007) but not before the intervention (r = 0.05, P = 0.84). In conclusion, these data show that exercise training improves resting substrate oxidation and creates a metabolic milieu that appears to promote lipid utilization in skeletal muscle, thus facilitating a reversal of insulin resistance. We also demonstrate that leptin sensitivity is improved but that such a trend may rely on reducing caloric intake in addition to exercise training.     

Molecular correlates for maximal oxygen uptake and type 1 fibers

Maximal oxygen uptake (Vo(2max)) and the amount of type 1 fibers are interrelated, but the underlying unifying molecular mechanisms are poorly understood. To explore these mechanisms, we related gene expression profiles in skeletal muscle biopsies of 43 age-matched men from published datasets with Vo(2max) and the amount of type 1 fibers and replicated some of the findings in muscle biopsies from 154 young and elderly individuals using real-time PCR. We identified 66 probe sets (genes or expressed sequence tags) positively and 83 probe sets inversely correlated with Vo(2max) and 171 probe sets positively and 217 probe sets inversely correlated with percentage of type 1 fibers in human skeletal muscle. Genes involved in oxidative phosphorylation (OXPHOS) showed high expression in individuals with high Vo(2max), whereas the opposite was not the case in individuals with low Vo(2max). Instead, genes such as AHNAK and BCL6 were associated with low Vo(2max). Also, expression of the OXPHOS genes NDUFB5 and ATP5C1 increased with exercise training and decreased with aging. In contrast, expression of AHNAK in skeletal muscle decreased with exercise training and increased with aging. Eleven genes (NDUFB4, COX5A, UQCRB, ATP5C1, ATP5G3, ETHE1, FABP3, ISCA1, MYST4, C9orf3, and PKIA) were positively correlated with both Vo(2max) and the percentage of type 1 fibers. Vo(2max) closely reflects expression of OXPHOS genes, particularly that of NDUFB5 and ATP5C1, in skeletal muscle, suggesting good muscle fitness. In contrast, a high expression of AHNAK was associated with a low Vo(2max) and poor muscle fitness.     

Skeletal muscle creatine kinase MB alterations in women marathon runners

Total creatine kinase (CK) and CK MB activities were determined in gastrocnemius muscle and serum obtained from 14 female marathon runners. The level of CK MB in muscle increased significantly (p less than 0.05) after chronic exercise training from 5.3% to 10.5% of the total CK activity, but not after acute exercise (post-marathon 8.9%). No significant differences in total CK activities were detected. However, the total CK activity in the muscles were significantly (p less than 0.05) less than those previously reported from the muscle of men runners (1800 U/g, 3000 U/g respectively). No significant correlation existed between fiber type and muscle CK MB activity. Additionally, trace amounts of mitochondrial CK and CK BB were present in muscle homogenates. A significant correlation was observed in the increase in mean serum total CK (597 UL-1) and CK MB (23 UL-1) activities 24 h after the race (r = 0.97, p less than 0.05). These results suggest that gastrocnemius muscle in women adapts to training with increased CK MB activities and imply that skeletal muscle is the major source of elevated serum CK MB activities in women marathon runners.     

Creatine kinase-MB isoenzyme adaptations in stressed human skeletal muscle of marathon runners

The creatine kinase (CK) isoenzyme composition was determined in serial gastrocnemius muscle biopsies obtained from 12 male marathon runners. The mean muscle CK-MB composition significantly increased after chronic exercise (training) from 5.3% (pretraining) to 7.7% (premarathon) as well as after acute exercise (postmarathon) to 10.5% of the total CK activity (P less than 0.05). However, no significant differences in total CK activities were detected. Additionally, mitochondrial CK and CK-BB isoenzymes were present in muscle homogenates. A significant correlation was observed in the increase in mean serum total CK (3,322 U/l) and CK-MB (174 U/l) activities 24 h after the race (r = 0.98, P less than 0.05). These results show that gastrocnemius muscle adapts to long-distance training and racing with increased CK-MB activities and imply that skeletal muscle is the major source of elevated serum CK-MB activities in marathon runners.     

Aging attenuates vascular and metabolic plasticity but does not limit improvement in muscle VO(2) max

The interactions between exercise, vascular and metabolic plasticity, and aging have provided insight into the prevention and restoration of declining whole body and small muscle mass exercise performance known to occur with age. Metabolic and vascular adaptations to normoxic knee-extensor exercise training (1 h 3 times a week for 8 wk) were compared between six sedentary young (20 +/- 1 yr) and six sedentary old (67 +/- 2 yr) subjects. Arterial and venous blood samples, in conjunction with a thermodilution technique facilitated the measurement of quadriceps muscle blood flow and hematologic variables during incremental knee-extensor exercise. Pretraining, young and old subjects attained a similar maximal work rate (WR(max)) (young = 27 +/- 3, old = 24 +/- 4 W) and similar maximal quadriceps O(2) consumption (muscle Vo(2 max)) (young = 0.52 +/- 0.03, old = 0.42 +/- 0.05 l/min), which increased equally in both groups posttraining (WR(max), young = 38 +/- 1, old = 36 +/- 4 W, Muscle Vo(2 max), young = 0.71 +/- 0.1, old = 0.63 +/- 0.1 l/min). Before training, muscle blood flow was approximately 500 ml lower in the old compared with the young throughout incremental knee-extensor exercise. After 8 wk of knee-extensor exercise training, the young reduced muscle blood flow approximately 700 ml/min, elevated arteriovenous O(2) difference approximately 1.3 ml/dl, and increased leg vascular resistance approximately 17 mmHg x ml(-1) x min(-1), whereas the old subjects revealed no training-induced changes in these variables. Together, these findings indicate that after 8 wk of small muscle mass exercise training, young and old subjects of equal initial metabolic capacity have a similar ability to increase quadriceps muscle WR(max) and muscle Vo(2 max), despite an attenuated vascular and/or metabolic adaptation to submaximal exercise in the old.     

Greater rate of decline in maximal aerobic capacity with age in endurance-trained than in sedentary men.

To determine the relation between habitual endurance exercise status and the age-associated decline in maximal aerobic capacity [i.e., maximal O(2) consumption (Vo(2 max))] in men, we performed a well-controlled cross-sectional laboratory study on 153 healthy men aged 20-75 yr: 64 sedentary and 89 endurance trained. Vo(2 max) (ml. kg(-1). min(-1)), measured by maximal treadmill exercise, was inversely related to age in the endurance-trained (r = -0.80) and sedentary (r = -0.74) men but was higher in the endurance-trained men at any age. The rate of decline in Vo(2 max) with age (ml. kg(-1). min(-1)) was greater (P < 0.001) in the endurance-trained than in the sedentary men. Whereas the relative rate of decline in Vo(2 max) (percent decrease per decade from baseline levels in young adulthood) was similar in the two groups, the absolute rate of decline in Vo(2 max) was -5.4 and -3.9 ml. kg(-1). min(-). decade(-1) in the endurance-trained and sedentary men, respectively. Vo(2 max) declined linearly across the age range in the sedentary men but was maintained in the endurance-trained men until approximately 50 yr of age. The accelerated decline in Vo(2 max) after 50 yr of age in the endurance-trained men was related to a decline in training volume (r = 0.46, P < 0.0001) and was associated with an increase in 10-km running time (r = -0.84, P < 0.0001). We conclude that the rate of decline in maximal aerobic capacity during middle and older age is greater in endurance-trained men than in their sedentary peers and is associated with a marked decline in O(2) pulse.     

Regular exercise enhances insulin activation of IRS-1-associated PI3-kinase in human skeletal muscle.

Insulin action in skeletal muscle is enhanced by regular exercise. Whether insulin signaling in human skeletal muscle is affected by habitual exercise is not well understood. Phosphatidylinositol 3-kinase (PI3-kinase) activation is an important step in the insulin-signaling pathway and appears to regulate glucose metabolism via GLUT-4 translocation in skeletal muscle. To examine the effects of regular exercise on PI3-kinase activation, 2-h hyperinsulinemic (40 mU. m(-2). min(-1))-euglycemic (5.0 mM) clamps were performed on eight healthy exercise-trained [24 +/- 1 yr, 71.8 +/- 2.0 kg, maximal O(2) uptake (VO(2 max)) of 56.1 +/- 2.5 ml. kg(-1). min(-1)] and eight healthy sedentary men and women (24 +/- 1 yr, 64.7 +/- 4.4 kg, VO(2 max) of 44.4 +/- 2.7 ml. kg(-1). min(-1)). A [6, 6-(2)H]glucose tracer was used to measure hepatic glucose output. A muscle biopsy was obtained from the vastus lateralis muscle at basal and at 2 h of hyperinsulinemia to measure insulin receptor substrate-1(IRS-1)-associated PI3-kinase activation. Insulin concentrations during hyperinsulinemia were similar for both groups (293 +/- 22 and 311 +/- 22 pM for trained and sedentary, respectively). Insulin-mediated glucose disposal rates (GDR) were greater (P < 0.05) in the exercise-trained compared with the sedentary control group (9.22 +/- 0.95 vs. 6.36 +/- 0.57 mg. kg fat-free mass(-1). min(-1)). Insulin-stimulated PI3-kinase activation was also greater (P < 0.004) in the trained compared with the sedentary group (3.8 +/- 0.5- vs. 1.8 +/- 0.2-fold increase from basal). Endurance capacity (VO(2 max)) was positively correlated with PI3-kinase activation (r = 0.53, P < 0.04). There was no correlation between PI3-kinase and muscle morphology. However, increases in GDR were positively related to PI3-kinase activation (r = 0.60, P < 0.02). We conclude that regular exercise leads to greater insulin-stimulated IRS-1-associated PI3-kinase activation in human skeletal muscle, thus facilitating enhanced insulin-mediated glucose uptake.     

Effect of interval versus continuous training on cardiorespiratory and mitochondrial functions: relationship to aerobic performance improvements in sedentary subjects

The goal of the study was to determine the effects of continuous (CT) vs. intermittent (IT) training yielding identical mechanical work and training duration on skeletal muscle and cardiorespiratory adaptations in sedentary subjects. Eleven subjects (6 men and 5 women, 45 +/- 3 years) were randomly assigned to either of the two 8-wk training programs in a cross-over design, separated by 12 wk of detraining. Maximal oxygen uptake (Vo2max) increased after both trainings (9% with CT vs. 15% with IT), whereas only IT was associated with faster Vo2 kinetics (tau: 68.0 +/- 1.6 vs. 54.9 +/- 0.7 s, P < 0.05) measured during a test to exhaustion (TTE) and with improvements in maximal cardiac output (Qmax, from 18.1 +/- 1.1 to 20.1 +/- 1.2 l/min; P < 0.01). Skeletal muscle mitochondrial oxidative capacities (Vmax) were only increased after IT (3.3 +/- 0.4 before and 4.5 +/- 0.6 micromol O2 x min(-1) x g dw(-1) after training; P < 0.05), whereas capillary density increased after both trainings, with a two-fold higher enhancement after CT (+21 +/- 1% for IT and +40 +/- 3% after CT, P < 0.05). The gain of Vmax was correlated with the gain of TTE and the gain of Vo2max with IT. The gain of Qmax was also correlated with the gain of VO2max. These results suggest that fluctuations of workload and oxygen uptake during training sessions, rather than exercise duration or global energy expenditure, are key factors in improving muscle oxidative capacities. In an integrative view, IT seems optimal in maximizing both peripheral muscle and central cardiorespiratory adaptations, permitting significant functional improvement. These data support the symmorphosis concept in sedentary subjects.     

Mitochondrial creatine kinase activity alterations in skeletal muscle during long-distance running

In human gastrocnemius muscle obtained from long-distance runners, mitochondrial creatine kinase (CK) activities were significantly greater than nonrunning control skeletal muscle and significantly increased during training for and after a marathon race. Thus skeletal muscle tended to become similar to heart muscle in its mitochondrial CK composition. Total muscle CK activity was significantly different in males and females, was unaffected by marathon training and racing, and was similar to gastrocnemius muscle obtained from nonrunning controls. There was an inverse correlation between the maximum O2 uptake and the percentage increase in mitochondrial CK activity after training. These studies suggest that mitochondrial CK may play a key role in the intracellular transport of energy from mitochondrial to myofibrils in skeletal muscle during endurance exercise such as long-distance running.     

Exercise training increases intramyocellular lipid and oxidative capacity in older adults

Intramyocellular lipid (IMCL) has been associated with insulin resistance. However, an association between IMCL and insulin resistance might be modulated by oxidative capacity in skeletal muscle. We examined the hypothesis that 12 wk of exercise training would increase both IMCL and the oxidative capacity of skeletal muscle in older (67.3 +/- 0.7 yr), previously sedentary subjects (n = 13; 5 men and 8 women). Maximal aerobic capacity (Vo(2 max)) increased from 1.65 +/- 0.20 to 1.85 +/- 0.14 l/min (P < 0.05), and systemic fat oxidation induced by 1 h of cycle exercise at 45% of Vo(2 max) increased (P < 0.05) from 15.03 +/- 40 to 19.29 +/- 0.80 (micromol.min(-1).kg fat-free mass(-1)). IMCL, determined by quantitative histological staining in vastus lateralis biopsies, increased (P < 0.05) from 22.9 +/- 1.9 to 25.9 +/- 2.6 arbitrary units (AU). The oxidative capacity of muscle, determined by succinate dehydrogenase staining intensity, significantly increased (P < 0.05) from 75.2 +/- 5.2 to 83.9 +/- 3.6 AU. The percentage of type I fibers significantly increased (P < 0.05) from 35.4 +/- 2.1 to 40.1 +/- 2.3%. In conclusion, exercise training increases IMCL in older persons in parallel with an enhanced capacity for fat oxidation.     

Mitochondrial DNA Mutations Induce Mitochondrial Dysfunction,Apoptosis and Sarcopenia in Skeletal Muscle of Mitochondrial DNA Mutator Mice

Background

Aging results in a progressive loss of skeletal muscle, a condition known as sarcopenia. Mitochondrial DNA (mtDNA) mutations accumulate with aging in skeletal muscle and correlate with muscle loss, although no causal relationship has been established.

Methodology/Principal Findings

We investigated the relationship between mtDNA mutations and sarcopenia at the gene expression and biochemical levels using a mouse model that expresses a proofreading-deficient version (D257A) of the mitochondrial DNA Polymerase γ, resulting in increased spontaneous mtDNA mutation rates. Gene expression profiling of D257A mice followed by Parametric Analysis of Gene Set Enrichment (PAGE) indicates that the D257A mutation is associated with a profound downregulation of gene sets associated with mitochondrial function. At the biochemical level, sarcopenia in D257A mice is associated with a marked reduction (35–50%) in the content of electron transport chain (ETC) complexes I, III and IV, all of which are partly encoded by mtDNA. D257A mice display impaired mitochondrial bioenergetics associated with compromised state-3 respiration, lower ATP content and a resulting decrease in mitochondrial membrane potential (Δψ_m). Surprisingly, mitochondrial dysfunction was not accompanied by an increase in mitochondrial reactive oxygen species (ROS) production or oxidative damage.

Conclusions/Significance

These findings demonstrate that mutations in mtDNA can be causal in sarcopenia by affecting the assembly of functional ETC complexes, the lack of which provokes a decrease in oxidative phosphorylation, without an increase in oxidative stress, and ultimately, skeletal muscle apoptosis and sarcopenia.     

Aerobic power declines with aging in rat skeletal muscles perfused at matched convective O2 delivery.

Although it is well established that maximal O(2) uptake (Vo(2 max)) declines from adulthood to old age, the role played by alterations in skeletal muscle is unclear. Specifically, because during whole body exercise reductions in convective O(2) delivery to the working muscles from adulthood to old age compromise aerobic performance, this obscures the influence of alterations within the skeletal muscles. We sought to overcome this limitation by using an in situ pump-perfused hindlimb preparation to permit matching of muscle convective O(2) delivery in young adult (8 mo; muscle convective O(2) delivery = 569 +/- 42 micromol O(2) x min(-1) x 100 g(-1)) and late middle-aged (28-30 mo; 539 +/- 62 micromol O(2) x min(-1) x 100 g(-1)) Fischer 344 x Brown Norway F1 hybrid rats. The distal hindlimb muscles were electrically stimulated for 4 min (60 tetani/min), and Vo(2 max) was determined. Vo(2 max) normalized to the contracting muscle mass was 22% lower in the 28- to 30-mo-old (344 +/- 17 micromol O(2). min(-1) x 100 g(-1)) than the 8-mo-old (441 +/- 20 micromol O(2) x min(-1) x 100 g(-1); P < 0.05) rats. The flux through the electron transport chain complexes I-III was 45% lower in homogenates prepared from the plantaris muscles of the older animals. Coincident with these alterations, the tension at Vo(2 max) and lactate efflux were reduced in the 28- to 30-mo-old animals, whereas the percent decline in tension was greater in the 28- to 30-mo-old vs. 8-mo-old animals. Collectively, these results demonstrate that alterations within the skeletal muscles, such as a reduced mitochondrial oxidative capacity, contribute to the reduction in Vo(2 max) with aging.     

Effects of Weight Loss and Physical Activity on Muscle Lipid Content and Droplet Size

Objectives : To address the potential effects of weight loss and physical activity (WL + Ex) on intramyocellular lipid (IMCL) and lipid droplet size in overweight and obese previously sedentary individuals. Research Methods and Procedures : IMCL and lipid droplet size was determined in vastus lateralis, obtained by percutaneous biopsy, from 21 obese volunteers (9 men/12 women), using Oil Red O staining, along with succinate dehydrogenase histochemistry and mitochondrial immunohistochemistry as measures of skeletal muscle oxidative capacity. Insulin sensitivity (IS) was determined by glucose clamp. Results : A 4‐month WL + Ex intervention resulted in ～10% WL and ～15% increase in maximal oxygen uptake, leading to a 46% increase in IS (all p < 0.01). IMCL did not significantly change (p = 0.36). However, the size of lipid droplets decreased after WL + Ex (p < 0.01), and this decrease in lipid droplet size correlated with increased IS (p < 0.01) and the amount of physical activity (p < 0.05). Succinate dehydrogenase activity and mitochondrial labeling increased significantly (p < 0.01), without a significant shift in fiber type distribution. Discussion : In summary, IMCL does not decrease in response to WL + Ex in obese, previously sedentary individuals, yet the lipid within muscle is dispersed into smaller droplets. This change in the size of lipid droplets, likely coupled with a concomitant increase in oxidative enzyme capacity, is correlated to improved IS.     

Effect of voluntary exercise on H2O2 release by subsarcolemmal and intermyofibrillar mitochondria

Previous data have demonstrated that, to handle the oxidative stress encountered with training at high intensity, skeletal muscle relies on an increase in mitochondrial biogenesis, a reduced H(2)O(2) production, and an enhancement of antioxidant enzymes. In the present study, we evaluated the influence of voluntary running on mitochondrial O(2) consumption and H(2)O(2) production by intermyofibrillar mitochondria (IFM) and subsarcolemmal mitochondria (SSM) isolated from oxidative muscles in conjunction with the determination of antioxidant capacities. When mitochondria are incubated with succinate as substrate, both maximal (state 3) and resting (state 4) O(2) consumption were significantly lower in SSM than in IFM populations. Mitochondrial H(2)O(2) release per unit of O(2) consumed was 2-fold higher in SSM than in IFM. Inhibition of H(2)O(2) formation by rotenone suggests that complex I of the electron transport chain is likely the major physiological H(2)O(2)-generating system. In Lou/C rats (an inbred strain of rats of Wistar origin), neither O(2) consumption nor H(2)O(2) release by IFM and SSM were affected by long-term, voluntary wheel training. In contrast, glutathione peroxidase and catalase activity were significantly increased despite no change in oxidative capacities with long-term, voluntary exercise. Furthermore, chronic exercise enhanced heat shock protein 72 accumulation within skeletal muscle. It is concluded that the antioxidant status of muscle can be significantly improved by prolonged wheel exercise without necessitating an increase in mitochondrial oxidative capacities.     

Effects of exercise training on acclimatization to hypoxia: systemic O2 transport during maximal exercise.

Acclimatization to hypoxia has minimal effect on maximal O2 uptake (Vo2 max). Prolonged hypoxia shows reductions in cardiac output (Q), maximal heart rate (HR-max), myocardial beta-adrenoceptor (beta-AR) density, and chronotropic response to isoproterenol. This study tested the hypothesis that exercise training (ET), which attenuates beta-AR downregulation, would increase HRmax and Q of acclimatization and result in higher Vo2 max. After 3 wk of ET, rats lived at an inspired Po2 of 70 Torr for 10 days (acclimatized trained rats) or remained in normoxia, while both groups continued to train in normoxia. Controls were sedentary acclimatized and nonacclimatized rats. All rats exercised maximally in normoxia and hypoxia (inspired Po2 of 70 Torr). Myocardial beta-AR density and the chronotropic response to isoproterenol were reduced, and myocardial cholinergic receptor density was increased after acclimatization; all of these receptor changes were reversed by ET. Normoxic Vo2 max (in ml.min-1.kg-1) was 95.8 +/- 1.0 in acclimatized trained (n = 6), 87.7 +/- 1.7 in nonacclimatized trained (P < 0.05, n = 6), 74.2 +/- 1.4 in acclimatized sedentary (n = 6, P < 0.05), and 72.5 +/- 1.2 in nonacclimatized sedentary (n = 8; P > 0.05 acclimatized sedentary vs. nonacclimatized sedentary). A similar distribution of Vo2 max values occurred in hypoxic exercise. Q was highest in trained acclimatized and nonacclimatized, intermediate in nonacclimatized sedentary, and lowest in acclimatized sedentary groups. ET preserved Q in acclimatized rats thanks to maintenance of HRmax as well as of maximal stroke volume. Q preservation, coupled with a higher arterial O2 content, resulted in the acclimatized trained rats having the highest convective O2 transport and Vo2 max. These results show that ET attenuates beta-AR downregulation and preserves Q and Vo2 max after acclimatization, and support the idea that beta-AR downregulation partially contributes to the limitation of Vo2 max after acclimatization in rats.     

Similar qualitative and quantitative changes of mitochondrial respiration following strength and endurance training in normoxia and hypoxia in sedentary humans

Endurance and strength training are established as distinct exercise modalities, increasing either mitochondrial density or myofibrillar units. Recent research, however, suggests that mitochondrial biogenesis is stimulated by both training modalities. To test the training "specificity" hypothesis, mitochondrial respiration was studied in permeabilized muscle fibers from 25 sedentary adults after endurance (ET) or strength training (ST) in normoxia or hypoxia [fraction of inspired oxygen (Fi(O(2))) = 21% or 13.5%]. Biopsies were taken from the musculus vastus lateralis, and cycle-ergometric incremental maximum oxygen uptake (VO(2max)) exercise tests were performed under normoxia, before and after the 10-wk training program. The main finding was a significant increase (P < 0.05) of fatty acid oxidation capacity per muscle mass, after endurance and strength training under normoxia [2.6- and 2.4-fold for endurance training normoxia group (ET(N)) and strength training normoxia group (ST(N)); n = 8 and 3] and hypoxia [2.0-fold for the endurance training hypoxia group (ET(H)) and strength training hypoxia group (ST(H)); n = 7 and 7], and higher coupling control of oxidative phosphorylation. The enhanced lipid oxidative phosphorylation (OXPHOS) capacity was mainly (87%) due to qualitative mitochondrial changes increasing the relative capacity for fatty acid oxidation (P < 0.01). Mitochondrial tissue-density contributed to a smaller extent (13%), reflected by the gain in muscle mass-specific respiratory capacity with a physiological substrate cocktail (glutamate, malate, succinate, and octanoylcarnitine). No significant increase was observed in mitochondrial DNA (mtDNA) content. Physiological OXPHOS capacity increased significantly in ET(N) (P < 0.01), with the same trend in ET(H) and ST(H) (P < 0.1). The limitation of flux by the phosphorylation system was diminished after training. Importantly, key mitochondrial adaptations were similar after endurance and strength training, regardless of normoxic or hypoxic exercise. The transition from a sedentary to an active lifestyle induced muscular changes of mitochondrial quality representative of mitochondrial health.     

Training-induced changes in skeletal muscle Na+-K+ pump number and isoform expression in rats with chronic heart failure.

The mechanisms responsible for the decrements in exercise performance in chronic heart failure (CHF) remain poorly understood, but it has been suggested that sarcolemmal alterations could contribute to the early onset of muscular fatigue. Previously, our laboratory demonstrated that the maximal number of ouabain binding sites (B(max)) is reduced in the skeletal muscle of rats with CHF (Musch TI, Wolfram S, Hageman KS, and Pickar JG. J Appl Physiol 92: 2326-2334, 2002). These reductions may coincide with changes in the Na(+)-K(+)-ATPase isoform (alpha and beta) expression. In the present study, we tested the hypothesis that reductions in B(max) would coincide with alterations in the alpha- and beta-subunit expression of the sarcolemmal Na(+)-K(+)-ATPase of rats with CHF. Moreover, we tested the hypothesis that exercise training would increase B(max) along with producing significant changes in alpha- and beta-subunit expression. Rats underwent a sham operation (sham; n = 10) or a surgically induced myocardial infarction followed by random assignment to either a control (MI; n = 16) or exercise training group (MI-T; n = 16). The MI-T rats performed exercise training (ET) for 6-8 wk. Hemodynamic indexes demonstrated that MI and MI-T rats suffered from severe left ventricular dysfunction and congestive CHF. Maximal oxygen uptake (Vo(2 max)) and endurance capacity (run time to fatigue) were reduced in MI rats compared with sham. B(max) in the soleus and plantaris muscles and the expression of the alpha(2)-isoform of the Na(+)-K(+)-ATPase in the red portion of the gastrocnemius (gastrocnemius(red)) muscle were reduced in MI rats. After ET, Vo(2 max) and run time to fatigue were increased in the MI-T group of rats. This coincided with increases in soleus and plantaris B(max) and the expression of the alpha(2)-isoform in the gastrocnemius(red) muscle. In addition, the expression of the beta(2)-isoform of the gastrocnemius(red) muscle was increased in the MI-T rats compared with their sedentary counterparts. This study demonstrates that CHF-induced alterations in skeletal muscle Na(+)-K(+)-ATPase, including B(max) and isoform expression, can be partially reversed by ET.