Exercise training regulation of extracellular matrix and remodeling in the aging rat heart

Aging is characterized by a progressive impairment of cardiac structure and function. The cardiac remodeling involves loss of cardiac myocytes, reactive hypertrophy of the remaining cells, and increased extracellular matrix (ECM) and fibrosis in the aging heart. In contrast, exercise training not only improves cardiac function, but also reduces the risk of heart disease. However, the ability of exercise training to modulate ECM and remodeling in the aging heart remains unknown. Therefore, the purpose of this study was to determine the effects of exercise training on ECM remodeling in the aging heart. We hypothesized that (1) exercise training would attenuate age-related changes in left ventricle morphology including extramyocyte space and collagen contents, and (2) exercise training would ameliorate age-induced changes in ECM-related factors including MMPs, TIMPs, TNF-α, TGF-β1, and α-SMA in the heart. Three and 31 month old Fischer 344 × Brown Norway F1 hybrid rats were assigned to four groups: young sedentary (YS), young exercise-trained (YE), old sedentary (OS), and old exercise-trained (OE). Exercise training groups walked briskly on a treadmill for 45 min/day (12° incline) at 20m/min (young) or 10 m/min (old), 5 d/wk for 12 wk. We found that endurance exercise training might ameliorate the ageinduced increase in extramyocyte space and collagen contents of the left ventricle. Exercise training might protect against age-induced fibrosis by increasing MMP-2, MMP-14 in the soluble fraction and MMP-1, MMP-3, MMP-14 in the insoluble fraction of old rat hearts. Conversely, exercise training might reduce the fibrosis by decreasing TIMP-1 in the soluble fraction of old rat hearts. Further, exercise training reduced potential upstream pro-fibrotic mediators including TNF-α and TGF-β1 in the aging rat hearts. These results are the first to demonstrate that exercise training has a protective effect against age-induced extracellular collagen matrix remodeling in the aging heart, associated with increased MMP-1, -2, -3, -14 and decreased TIMP-1, TNF-α, and TGF- β1

Exercise training modulates apoptotic signaling in the aging rat heart

Aging is characterized by a progressive decline in cardiac function. A critical contributor to the age-related impairment in heart function is the loss of cardiac myocytes through ??apoptosis??, or programmed cell death. A dramatic increase in the rate of apoptosis has been reported with aging in the rat left ventricle. In contrast, exercise training not only improves cardiac function, but also reduces the risk of heart disease. However, the ability of exercise training to modulate apoptotic signaling and apoptosis in the aging heart remains unknown. Therefore, the purpose of this study was to determine the effects of exercise training on apoptotic signaling and apoptosis in the aging heart. We hypothesized that (1) aging would increase pro-apoptotic signaling and apoptosis in the rat left ventricle, and (2) exercise training would ameliorate upregulation of Bcl-2 family-driven apoptosis in the heart. Four and 25 month old Fischer-344 rats were assigned to four groups: young control (YC), young trained (YT), old control (OC), and old trained (OT). Exercise training groups ran on a treadmill for 60 min/day at 15 m/min (15˚ incline), 5 d/wk for 12 wk. Protein expression of Bax, Bcl-2, caspase-9, and cleaved caspase-3 was measured using Western immunoblot analysis. Apoptosis (DNA fragmentation) was assessed using a cell death detection ELISA. Bax levels in OC were dramatically higher (+176.0%) compared to YC. In contrast, exercise training resulted in a significant decrease (-53.4%) in Bax in OT compared to OC. Bcl-2 levels in OC were lower (-26.3%) compared to YC. Conversely, exercise training significantly increased Bcl-2 levels by 117.8% in OT compared to OC. Caspase-9 levels were higher (+98.7%) in OC than YC, while exercise training significantly reduced caspase-9 levels in YT (-52.6%) and OT (-76.9%), respectively. Aging resulted in a dramatic increase (+122.8%) in cleaved caspase-3 levels and a significant decrease (-32.9%) with exercise training. Finally, apoptosis (DNA fragmentation) significantly increased (+163.8%) with aging and decreased (-43.9%) with exercise training. These novel data indicate that aging increases pro-apoptotic signaling and apoptosis in the left ventricle, while exercise training is effective in diminishing pro-apoptotic signaling and apoptosis in the aging heart

The Effects of a NAD(P)H Oxidase Inhibition on Matrix Metalloproteinases and TIMP-1 in the MDX Diaphragm

Duchenne muscular dystrophy (DMD) is characterized by devastating muscle degeneration that includes oxidative stress, loss of contractile tissue, muscle weakness and increased fibrosis in respiratory muscles (e.g., diaphragm). The mdx mice diaphragm undergoes a progressive degeneration similar to that occurring in patients with DMD. We showed that apocynin, a NAD(P)H oxidase inhibitor, protects against reduction in diaphragm mass, oxidative capacity, and apoptosis. We hypothesized that apocynin (1.5mmol/L per day) would attenuate extramyocyte space and collagen content by ameliorating matrix metalloproteinases (e.g., MMP-2, MMP-9), tissue inhibitors of metalloproteinases (e.g., TIMP-1) and transforming growth factor-β (TGF-β) in the mdx diaphragm. Eight to nine week old mdx mice and age-matched C57BL wild-types were divided into 4 groups: wild-type controls + water (WW, n=7); wild-type controls + apocynin (WA, n=7); mdx mice + water (MW, n=7), and mdx mice + apocynin (MA, n=7). After 8 days of treatment, the diaphragm was extracted. Both MMP-2 (-22.6%) and MMP-9 (-27.8%) were lower in MW than WW. TIMP-1 (+61.3 %) and TGF-beta levels (+39.4%) were higher in MW than WW. MMP-2 (-21.8%) and TIMP-1 (-8.5%) levels were significantly decreased with apocynin in the mdx diaphragm. Our findings indicate cell protection of apocynin against fibrosis in the mdx diaphragm by regulating the protein levels of MMP-2/9 and TIMP-1

Exercise Ameliorates Disruption of the Dystrophin-Associated Glycoprotein Complex and Fibrosis in the Aging Rat Heart

The dystrophin-glycoprotein complex (DGC) is localized and integrated into the cell membrane. The DGC provides a mechanical link between the cellular cytoskeleton and the extracellular matrix (ECM). In cardiac muscle, disruption of DGC might be involved in mediating cardiac remodeling that occurs with aging, cardiomyopathy, and heart failure through transforming growth factor-beta (TGF-ß). Decorin is a small leucine-rich proteoglycan closely related to the DGC component that binds to collagen. Decorin reduces fibrosis via inhibition of TGF-ß and myofibroblast formation. PURPOSE: To test the hypothesis that exercise training (ET) would alleviate age-related disruption of localization in DGC proteins (dystrophin, α-syntrophin, and β-sarcoglycan), and ET will upregulate decorin. METHODS: Young (3 mo.) and old (31 mo.) FBNF1 rats were assigned into sedentary (YS, OS) and exercise (YE, OE) groups (n=10/group), with ET rats training on a treadmill 45 min/d, 5 d/wk for 12 wk. Hearts were extracted, weighted, and dissected into the left ventricle (LV), septum, and right ventricle. LV and septa samples were homogenized, and protein expression was detected using western immunoblotting. Histology (H&E staining) and immunofluorescence were conducted to examine morphological changes and localization of DGC proteins, decorin, α-SMA, and TGF-ß. Aging and exercise comparisons were made using two-way ANOVA for repeated measure with Fisher’s LSD post hoc test (p\u3c.05). RESULTS: Dystrophin, α-syntrophin, and β-sarcoglycan in LV were delocalized from the membrane with aging, particularly in fibrotic areas, which was normalized by ET. LVs from old rats displayed higher TGF-β-positive staining and protein abundance (+94.5%,p\u3c.05), while TGF-β localization and protein levels were suppressed in OE vs. OS, (-27.5%, p\u3c.05). α-SMA localization was significantly elevated with age (+77.3%, p\u3c.05), but reducedin old hearts with ET (-27.5%, p\u3c.05). Furthermore, collagen type 1 signal intensity was higher in OS (+43.7%, p\u3c.05), and was significantly ameliorated with ET (-27.6%, p\u3c.05). CONCLUSIONS: Our findings indicate that exercise training provides significant protection against fibrosis, myofibroblast activation, and elevation of TGF-ß associated with upregulation of decorin and protection of DGC structure

Effects of physical activity participation on cognitive impairment in older adults population with disabilities

BackgroundExisting research on the association between cognitive function and physical activity in the older adults population with disabilities is limited. Additionally, there is a need to explore avenues for enhancing the longevity and quality of life among these individuals.ObjectiveThis study aimed to investigate the independent and joint associations between cognitive function and levels of physical activity in the older adults population with disabilities.MethodsA total of 315 older adults adults (men = 182, women = 133), identified with disabilities based on medical evaluation, were recruited from the first survey of the Korean Longitudinal Study of Aging (KLoSA). Participants underwent assessments for cognitive function, physical activity (PA), activities of daily living (ADLs), instrumental activities of daily living (IADLs), and grip strength.ResultsADLs (p < 0.001) and IADLs (p < 0.001) scores were significantly higher in the male normal cognitive group compared to both the male and female cognitive impairment groups. In an unadjusted model, disabled older adults individuals who did not meet the recommended PA guidelines showed an increased odds ratio for cognitive dysfunction (OR = 2.29, 95% CI = 1.32–3.97). Those participating in PA at least 1 day per week also demonstrated an elevated odds ratio (OR = 1.22, 95% CI = 1.08–1.38) for cognitive dysfunction compared to those who engaged in regular PA. A negative correlation was observed between K-MMSE scores and grip strength (r = 0.448, p < 0.001).ConclusionThis study provides robust evidence that disabled older adults individuals who do not meet the recommended guidelines for PA or who do not participate in PA at least once a week have an increased likelihood of cognitive impairment compared to those who are regularly active

Overexpression of Long-Chain Acyl-CoA Synthetase 5 Increases Fatty Acid Oxidation and Free Radical Formation While Attenuating Insulin Signaling in Primary Human Skeletal Myotubes

In rodent skeletal muscle, acyl-coenzyme A (CoA) synthetase 5 (ACSL-5) is suggested to localize to the mitochondria but its precise function in human skeletal muscle is unknown. The purpose of these studies was to define the role of ACSL-5 in mitochondrial fatty acid metabolism and the potential effects on insulin action in human skeletal muscle cells (HSKMC). Primary myoblasts isolated from vastus lateralis (obese women (body mass index (BMI) = 34.7 ± 3.1 kg/m2)) were transfected with ACSL-5 plasmid DNA or green fluorescent protein (GFP) vector (control), differentiated into myotubes, and harvested (7 days). HSKMC were assayed for complete and incomplete fatty acid oxidation ([1-14C] palmitate) or permeabilized to determine mitochondrial respiratory capacity (basal (non-ADP stimulated state 4), maximal uncoupled (carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone (FCCP)-linked) respiration, and free radical (superoxide) emitting potential). Protein levels of ACSL-5 were 2-fold higher in ACSL-5 overexpressed HSKMC. Both complete and incomplete fatty acid oxidation increased by 2-fold (p < 0.05). In permeabilized HSKMC, ACSL-5 overexpression significantly increased basal and maximal uncoupled respiration (p < 0.05). Unexpectedly, however, elevated ACSL-5 expression increased mitochondrial superoxide production (+30%), which was associated with a significant reduction (p < 0.05) in insulin-stimulated p-Akt and p-AS160 protein levels. We concluded that ACSL-5 in human skeletal muscle functions to increase mitochondrial fatty acid oxidation, but contrary to conventional wisdom, is associated with increased free radical production and reduced insulin signaling

Effects of exercise on obesity-induced mitochondrial dysfunction in skeletal muscle

Obesity is known to induce inhibition of glucose uptake, reduction of lipid metabolism, and progressive loss of skeletal muscle function, which are all as- sociated with mitochondrial dysfunction in skeletal muscle. Mitochondria are dy- namic organelles that regulate cellular metabolism and bioenergetics, including ATP production via oxidative phosphorylation. Due to these critical roles of mitochon- dria, mitochondrial dysfunction results in various diseases such as obesity and type 2 diabetes. Obesity is associated with impairment of mitochondrial function (e.g., decrease in O2 respiration and increase in oxidative stress) in skeletal muscle. The bal- ance between mitochondrial fusion and fission is critical to maintain mitochondrial homeostasis in skeletal muscle. Obesity impairs mitochondrial dynamics, leading to an unbalance between fusion and fission by favorably shifting fission or reducing fusion proteins. Mitophagy is the catabolic process of damaged or unnecessary mito- chondria. Obesity reduces mitochondrial biogenesis in skeletal muscle and increases accumulation of dysfunctional cellular organelles, suggesting that mitophagy does not work properly in obesity. Mitochondrial dysfunction and oxidative stress are reported to trigger apoptosis, and mitochondrial apoptosis is induced by obesity in skeletal muscle. It is well known that exercise is the most effective intervention to protect against obesity. Although the cellular and molecular mechanisms by which exercise protects against obesity-induced mitochondrial dysfunction in skeletal mus- cle are not clearly elucidated, exercise training attenuates mitochondrial dysfunction, allows mitochondria to maintain the balance between mitochondrial dynamics and mitophagy, and reduces apoptotic signaling in obese skeletal muscle

Effects of 4-week Training Using Laboratory Index on Competition Record of Elite Female Middle-distance Runner: A Case Report

PURPOSE To investigate the effect of a 4-week training using a laboratory index on the competition record of elite female middle-distance runners. METHODS A female, middle-distance, trained runner with the following characteristics: age, 20 years; height, 168.7 cm; weight, 64.3 kg; 27.2% fat; and VO2max, 56.4 VO2 mL/kg/min; volunteered to participate in this study. Before the training program, the participant took part in a 1,500-m track and field national event in April and the onset of blood lactate threshold was analyzed using (OBVA/ vOBLA), VO2max/vVO2max, and tVO2max tests. After completing the 4-week training program, the participant again took part in the 1,500-m track and field national event in May and her parameters were reassessed using the OBVA/vOBLA, VO2max/vVO2max, and tVO2max tests. RESULTS Pre- and post-training indicate that vVO2max did not improve; however, tVO2max (206 seconds pre-training vs. 251.51 seconds post-training) and VO2max (56.4 vs. 59.3 VO2 mL/kg/min)significantly. However, this improvement in relative VO2 was due to weight loss, and the absolute value of VO2 (3.63 vs. 3.62 L/min) did not change. The 1,500-m race record in track and field events decreased significantly from a pre-training value of 5 minutes 03 seconds to a post-training value of 4 minutes 52 seconds. CONCLUSIONS The results of this study indicate that utilizing laboratory indicators including vOBLA, vVO2max, and tVO2max may be extremely valuable when prescribing training programs for middle-distance runners

Exercise Training Attenuates Ovariectomy-Induced Alterations in Skeletal Muscle Remodeling, Apoptotic Signaling, and Atrophy Signaling in Rat Skeletal Muscle

Purpose The effects of aerobic exercise training on soleus muscle morphology, mitochondria-mediated apoptotic signaling, and atrophy/hypertrophy signaling in ovariectomized rat skeletal muscle were investigated. Methods Female Sprague-Dawley rats were divided into control (CON), ovariectomy (OVX), and ovariectomy plus exercise (OVX+EX) groups. After ovarian excision, exercise training was performed using a rat treadmill at 20 m/min, 50 min/day, 5 days/week for 12 weeks. Protein levels of mitochondria-mediated apoptotic signaling and atrophy/hypertrophy signaling in the skeletal muscle (soleus) were examined through western immunoblot analysis. Results The number of myocytes and myocyte cross-sectional area (CSA) were increased and the extramyocyte space was decreased in the OVX group compared to those in the CON group. However, aerobic exercise training significantly increased myocyte CSA and decreased extramyocyte space in the OVX+EX group compared to those in the OVX group. The protein levels of proapoptotic signaling and muscle atrophy signaling were significantly increased, whereas the protein levels of muscle hypertrophy signaling were significantly decreased in the OVX group compared to that in the CON group. Aerobic exercise training significantly decreased the protein levels of proapoptotic signaling and increased the protein level of antiapoptotic protein in the OVX+EX group compared to that in the OVX group. Aerobic exercise training significantly increased the protein levels of hypertrophy signaling and decreased protein levels of atrophy signaling in the OVX+EX group compared to those in the OVX group. Conclusions Treadmill exercise improved estrogen deficiency-induced impairment in skeletal muscle remodeling, mitochondria-mediated apoptotic signaling, and atrophy/hypertrophy signaling in skeletal muscle

Treadmill Exercise Ameliorates Chemotherapy-Induced Muscle Weakness and Central Fatigue by Enhancing Mitochondrial Function and Inhibiting Apoptosis

Purpose Chemotherapy is associated with the side effects including damage to the mitochondrial DNA. Doxorubicin (DOX) serves as a chemotherapeutic agent for the patients with breast cancer or prostate cancer. DOX causes muscle weakness and fatigue. We investigated the effects of treadmill exercise on DOX-induced apoptosis and mitochondrial dysfunction in relation to central fatigue. For this study, we used the rat model of DOX-induced muscle damage. Methods DOX (2 mg/kg) was intraperitoneally injected 1 time per week for 4 weeks. Treadmill running continued 5 days per week for 4 weeks. Muscle strength and fatigue index in the gastrocnemius were measured. Immunohistochemistry for the expressions of tryptophan hydroxylase (TPH) and 5-hydroxytryptamine (5-HT) in the dorsal raphe was conducted. We used western blot analysis for the expressions of Bax, Bcl-2, and caspases-3 in the gastrocnemius. Mitochondrial function in the gastrocnemius was also evaluated. Results DOX treatment decreased muscle strength with increase of fatigue index in the gastrocnemius. Mitochondria function was deteriorated and apoptosis in the gastrocnemius was enhanced by DOX treatment. Expressions of TPH and 5-HT in the dorsal raphe were increased by DOX treatment. Treadmill exercise attenuated DOX-induced muscle fatigue and impairment of mitochondria function. Apoptosis in the gastrocnemius was inhibited and over-expression of TPH and 5-HT was suppressed by treadmill exercise. Conclusions Apoptosis was enhanced and mitochondria function was deteriorated by DOX treatment, resulting in muscle weakness and central fatigue. Treadmill exercise suppressed apoptosis and prevented deterioration of mitochondria function in muscle, resulting in alleviation of muscle weakness and central fatigue during DOX therapy