Increased tumor necrosis factor-alpha (TNF-alpha) levels have been found with age and are connected to muscle atrophy and cell loss, yet the signaling events that occur in vivo are unknown. Calorie restriction (CR), a robust intervention shown to repeatedly evade the physiological declines associated with aging, has been reported to reduce TNF-alpha and may assist in understanding the mechanisms of muscle sarcopenia. The effects of age and CR on muscle mass, myocyte area, fiber number, myocyte TNF-alpha expression, plasma TNF-alpha levels, and specific elements linked with the TNF-alpha signaling cascade (TNF-R1, IKKgamma, IkappaBalpha, p65, NF-kappaB binding activity, FADD, caspase-8, and DNA fragmentation) were investigated in soleus (predominately Type I fiber), and superficial vastus lateralis (SVL, predominately Type II fiber), of 6-month-old ad libitum fed (6AL), 26-month-old ad libitum fed (26AL), and 26-month-old calorie-restricted (26CR) male Fischer 344 rats (CR = 40% restriction compared with ad libitum). Plasma TNF-alpha was increased with age, and the age-associated rise was attenuated with life-long CR. In soleus muscle, we reported a greater capacity to cultivate inflammatory signaling through the transcription factor NF-kappaB compared with that detected in SVL with age. In contrast, in the SVL TNF-alpha stimulated apoptotic signaling with age to a much higher extent than was observed in the soleus. Moreover, a reduction in muscle mass, cross-sectional area, and fiber number in the SVL coincided with this age-linked elevation in apoptosis. In agreement with CR's ability, TNF-alpha stimulation of both inflammatory and apoptotic pathways were abrogated. Our results suggest that TNF-alpha signals transmitted to specific fiber types determine the decision of selecting life or death signaling pathways and are linked to the extent of fiber loss experienced in the aging muscle. Such a specific potential may constitute a major proponent in the pathogenesis of sarcopenia.

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This study suggested that exercise-induced inflammation, evaluated by changes in IL-6 and CRP, was significantly reduced by the dietary supplement.

-Evidence suggests that mitochondrial dysfunction and oxidant production, in association with an accumulation of oxidative damage, contribute to the aging process. Regular physical activity can delay the onset of morbidity, increase mean lifespan, and reduce the risk of developing several pathological states. No studies have examined age-related changes in oxidant production and oxidative stress in both subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria in combination with lifelong exercise. Therefore, we investigated whether long-term voluntary wheel running in Fischer 344 rats altered hydrogen peroxide (H 2O2) production, antioxidant defenses, and oxidative damage in cardiac SSM and IFM. At 10 -11 wk of age, rats were randomly assigned to one of two groups: sedentary and 8% food restriction (sedentary; n ϭ 20) or wheel running and 8% food restriction (runners; n ϭ 20); rats were killed at 24 mo of age. After the age of 6 mo, running activity was maintained at an average of 1,145 Ϯ 248 m/day. Daily energy expenditure determined by doubly labeled water technique showed that runners expended on average ϳ70% more energy per day than the sedentary rats. Long-term voluntary wheel running significantly reduced H 2O2 production from both SSM (Ϫ10.0%) and IFM (Ϫ9.6%) and increased daily energy expenditure (kJ/day) significantly in runners compared with sedentary controls. Additionally, MnSOD activity was significantly lowered in SSM and IFM from wheel runners, which may reflect a reduction in mitochondrial superoxide production. Activities of the other major antioxidant enzymes (glutathione peroxidase and catalase) and glutathione levels were not altered by wheel running. Despite the reduction in mitochondrial oxidant production, no significant differences in oxidative stress levels (4-hydroxy-2-nonenal-modified proteins, protein carbonyls, and malondialdehyde) were detected between the two groups. The health benefits of chronic exercise may be, at least partially, due to a reduction in mitochondrial oxidant production; however, we could not detect a significant reduction in several selected parameters of oxidative stress.

We investigated in vivo the chemotherapeutic anthracycline agents doxorubicin and its ability to activate mitochondrial-mediated, receptor-mediated and endoplasmic/ sarcoplasmic reticulum-mediated apoptosis transduction pathways in cardiac tissue from male and female rats. We administered a single low dose of doxorubicin (10 mg/kg of body weight, i.p.) and then isolated mitochondrial and cytosolic proteins one and four days later from the heart. Caspase-3 protein content and caspase-3 activity were significantly increased after day four of doxorubicin treatment in both male and female rats. However, while males had DNA fragmentation at day one but not day four following doxorubicin administration, females showed no significant increase in DNA fragmentation at either time. Caspase-12, localized in the SR, is considered a central caspase, and its activation by cleavage via calpain indicates activation of the SR-mediated pathway of apoptosis. Cleaved caspase-12 content and calpain activity significantly increased after day four of doxorubicin treatment in both sexes. In the mitochondrial-mediated pathway, there were no significant treatment effects observed in cytosolic cytochrome c and cleaved (active) caspase-9 in either sex. In control rats (saline injection), glutathione peroxidase (GPX) activity and hydrogen peroxide (H 2 O 2 ) production were lower in females compared to males. Doxorubicin treatment did not significantly affect H 2 O 2 , GPX activity or ATP production in isolated mitochondria in either sex. Female rats produced significantly lower levels of H 2 O 2 production one day after doxorubicin treatment, whereas male rats produced significantly less mitochondrial H 2 O 2 four days after doxorubicin treatment. The receptor-mediated pathway (caspase-8 and c-FLIP) showed no evidence of being significantly activated by doxorubicin treatment. Hence, doxorubicin-induced apoptosis in vivo is mediated by the SR to a greater extent than other apoptotic pathways and should therefore be considered for targeted therapeutic interventions. Moreover, no major sex differences exist in apoptosis signaling transduction cascade due to doxorubicin treatment.

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Objective-The goal of this study is to determine whether C-reactive protein (CRP) gene variants affect baseline and training-induced changes in plasma CRP levels. Methods and Results-Sixty-three sedentary men and women aged 50 to 75 years old underwent baseline testing (VOmax, body composition, CRP levels). They repeated these tests after 24 weeks of exercise training while on a low-fat diet. The CRP ϩ219G/A variant significantly associated with CRP levels before and after training after accounting for the effects of demographic and biological variables. CRP Ϫ732A/G genotype was significantly related on a univariate basis to CRP levels after training. The CRP ϩ29T/A variant did not affect CRP levels before or after training. In regression analyses, the ϩ219 and Ϫ732 variants each had significant effects on CRP levels before and after training. Subjects homozygous for the common A/G Ϫ732/ϩ219 haplotype exhibited the highest CRP levels, and having the rare allele at either site was associated with significantly lower CRP levels. CRP levels decreased significantly with training (Ϫ0.38Ϯ0.18 mg/L; Pϭ0.03). However, none of the CRP variants was associated with the training-induced CRP changes. Conclusion-CRP ϩ219G/A and Ϫ732A/G genotypes and haplotypes and exercise training appear to modulate CRP levels. However, training-induced CRP reductions appear to be independent of genotype at these loci. Key Words: C-reactive protein Ⅲ genetics Ⅲ exercise training A therosclerosis, which is the main mechanism underlying most cardiovascular (CV) diseases, is now considered to be, at least partly, an inflammatory disorder. C-reactive protein (CRP) has been proposed as a marker of inflammation, 1 with lower CRP levels associated with reduced CV disease risk 2 and even slight CRP elevations associated with increased CV events. 1 Cross-sectional studies have found that CRP levels are lowest in those with the highest levels of habitual physical activity; 3 however, very few studies have assessed the impact of an exercise training intervention on CRP levels. 4 See pages 1743 and 1868Recent evidence indicates that common polymorphisms at the CRP gene locus affect CRP levels. 5,6 Four single nucleotide polymorphisms (SNPs) have been identified in the CRP gene: Ϫ732 A/G, an adenine/guanine transition in the promoter region of the CRP gene; 7 ϩ29 T/A, a thymine/adenine transversion in intron 1, 29-bp downstream (3Ј) of exon 1; ϩ1059 G/C, a silent guanine/cytosine transversion in the exon 2 coding region; 8 and ϩ219 G/A, a guanine/adenine transition in the 3Ј flanking sequence of the CRP gene, 219-bp downstream (3Ј) of exon 2. Because genetic variations affect the responses of other CV disease risk factors to exercise training, 9,10 it is possible that these CRP gene variants may interact with exercise training to differentially affect plasma CRP levels. Thus, we hypothesized that CRP levels at baseline and after 6 months of exercise training will differ among CRP genotype groups, CRP levels will decrease as a result of exercise training,...

Objective: To investigate whether persistent ischaemic dysfunction of the myocardium after dynamic stress can be diagnosed from changes in ultrasonic strain rate and strain. Design: Prospective observational study, with age matched controls. Setting: University hospital. Patients and methods: 26 patients (23 men, mean (SD) age 58.9 (8.1) years) with coronary artery disease but no infarction and 12 controls (9 men, aged 56.1 (8.8) years) with normal coronary arteriography and negative exercise test underwent treadmill exercise (Bruce protocol). Tissue Doppler echocardiography was performed at baseline, at peak exercise, and at intervals up to one hour. Systolic and diastolic velocity, strain, and strain rate were recorded in the basal anterior segment of 16 patients with proximal left anterior descending coronary artery disease. Results: Patients developed ischaemia, since they experienced angina, exercised for less time, and reached a lower workload than the control group, and had ST segment depression (22.4 mm). Myocardial systolic velocity immediately after exercise increased by 31% and strain rate fell by 25% compared with increases of 92% and 62%, respectively, in the control group (p , 0.05). During recovery, myocardial systolic velocity and strain rate normalised quickly, whereas systolic strain remained depressed at 30 and 60 minutes after exercise, by 21% and 23%, respectively, compared with baseline (p , 0.05 versus controls). Myocardial diastolic velocities and strain rate normalised but early diastolic strain remained depressed by 32% compared with controls for 60 minutes (p , 0.05). Strain during atrial contraction was abnormal for 30 minutes. Conclusions: Myocardial strain shows regional post-ischaemic dysfunction in systole and diastole and may become a useful diagnostic tool in patients presenting with chest pain with a normal ECG.