bluuebunny/crossref_metadata_2025 huggingface dataset:
Ghrelin Ameliorates Doxorubicin‐induced Cardiomyopathy and Cardiac Fibrosis
Authors: Siu Parco M , Pei Xiao M , Benzie Iris F , Ying Michael
Published: June 2021

Doxorubicin (DOX)‐induced cardiac toxicity is a serious clinical concern. This study aimed to examine the effects of ghrelin, a natural brain‐gut peptide, on DOX‐induced cardiomyopathy and cardiac fibrosis. We tested the hypothesis that ghrelin can alleviate cardiomyopathy and cardiac fibrosis induced by DOX. Adult C57BL/6 mice were randomly assigned to Control, DOX, and DOX with ghrelin treatment groups. Mice in Control and DOX groups were exposed to a single i.p. injection of saline and 15 mg/kg of DOX, respectively. Twelve hours after DOX injection, mice in DOX with ghrelin treatment group were i.p. injected with 100 μg/kg of unacylated ghrelin twice a day for 4 days. Echocardiography was used to examine cardiac function. Mice were sacrificed and the left ventricle (LV) was used to examine cardiac fibrosis by Masson trichrome stain. RT‐PCR was used to examine the expression of fibrosis‐associated genes. According to our echocardiographic examination, DOX induced a decrease in LV fractional shortening and ejection fraction by 20% and 9%, respectively (p<0.01). Conversely, the DOX‐induced decrease in fractional shortening and ejection fraction were not found in mice treated with ghrelin. Our staining analysis indicated that the amount of cardiac fibrotic tissue was increased by DOX whereas ghrelin treatment prevented the DOX‐induced increase in cardiac fibrosis. CTGF mRNA content and the ratio of CTGF/BNP mRNA were increased by 520% and 121%, respectively, in ventricular muscle of DOX group when compared to Control group (p<0.01). In contrast, CTGF mRNA and the ratio of CTGF/BNP mRNA were reduced by 68% and 44%, respectively, in DOX with ghrelin treatment group when compared to DOX group (p<0.05). The mRNA contents of BNP, TGF‐beta and PAI‐1 were not significantly changed in all groups. Our data demonstrate that ghrelin attenuates the DOX‐induced ventricular dysfunction and cardiac fibrosis. These findings suggest that ghrelin might be a potential target for developing treatment for DOX‐induced cardiotoxicity.
Modulation of the ubiquitin proteasome system (UPS) in thyroid hormone‐induced cardiac hypertrophy
Authors: LINO CAROLINE ANTUNES , BARRETO-CHAVES MARIA LUIZA MORAES
Published: June 2021

The aim of this study is to evaluate the role of the ubiquitin proteasome system (UPS) in thyroid hormone (TH)‐induced cardiac hypertrophy. Experimental hyperthyroidism was induced in male Wistar rats by daily intraperitoneal injections of T3 (7 μg/100 g BW/day) for 21 days. The catalytic subunits of the proteasome were evaluated by real time RT‐PCR and the ubiquitinated proteins were analyzed by Western Blotting. The hyperthyroid status was confirmed by serum TH levels dosage by radioimmunoassay. As expected, the heart rate was increased in hyperthyroid animals from 7th day of treatment (n=3; p<0.001) as well as the cardiac mass, which increased about 31% compared to control (n=3; p<0.001). Although additional experiments need to be performed, the results indicate that there was an increase on gene expression of β1, β2 and β5 subunits of proteasome in hyperthyroid group, while the expression of ubiquitinated proteins remained unchanged when compared to control group. It remains to be clarified how this proteolytic system is modulated in hyperthyroidism condition and if this modulation could contribute to the development of TH‐induced cardiac hypertrophy. Source of Research Support: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES); Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP).
Role of AMPK in the cardiomyocyte hypertrophy induced by thyroid hormone (TH)
Authors: Takano Ana Paula Cremasco , Diniz Gabriela Placona , Barreto-Chaves Maria Luiza Morais
Published: June 2021

AMP‐activated protein kinase (AMPK) is a key regulator of cellular energy homeostasis and its activation may modulate protein synthesis. This study evaluated the effect of TH on the AMPK signaling pathway and the participation of this kinase on the cardiomyocyte hypertrophy. Cardiomyocytes cultures were prepared from ventricles of neonatal Wistar rats by enzymatic method. The cells were treated with T3 (10 nM) for 5, 10, 15, 30 min and 24 h and the AMPK signaling was analyzed by Western Blot. The cells were stimulated with Aicar (0.5 mM) for 24 h for analysis of contribution of AMPK on cardiac hypertrophy induced by T3 and classical parameters of hypertrophy were analyzed. Data were presented as mean±SD and were evaluated using one‐way analysis of variance. Values of P<0.05 were considered statistically significant. T3 rapidly increased the AMPK phosphorylation levels on Thr172 and partially increased the ACC, LKB1 and PP2C levels related to control cells. The AMPK activation by Aicar promoted a significant decrease on cardiomyocyte area, on leucine incorporation levels and on ANF and BNP mRNA levels, compared to T3‐ treated cells. In conclusion, data show that TH rapidly activates AMPK and suggest that the inhibition of protein synthesis by pharmacological activation of AMPK may be a key regulatory mechanism by which hypertrophic growth can be controlled. Financial Support: FAPESP and CNPq.
Circulating Insulin‐like Growth Factor‐1 (IGF‐1) is Associated with Vitamin A (VA) Status and Increased Circulating Hemoglobin (Hb) During Pregnancy in Nepalese Women
Authors: Arguello Margia A , Schulze Kerry J , Wu Lee S-F , Dreyfuss Michele L. , Christian Parul , West Keith P.
Published: June 2021

Erythropoiesis is compromised by vitamin A (VA) deficiency, and VA acts on the growth hormone/IGF‐1 axis. Whether VA works through IGF‐1 to enhance erythropoiesis in pregnancy has not been explored. We examined associations among mid‐pregnancy retinol, IGF‐1, iron status (ferritin and erythrocyte protoporphyrin) and Hb in 589 rural, pregnant, iron deficient women who participated in a placebo‐controlled VA and β‐carotene supplementation trial in Nepal. Associations of retinol to IGF‐1 and IGF‐1 to Hb or anemia were determined with linear and logistic regression. Path analysis was used to evaluate IGF‐1 as a mediator between retinol and Hb, acting through or independently of iron status indicators. The interventions modestly increased IGF‐1 (P = 0.09 for ANOVA), while each 0.1 μmol/L increment in retinol increased IGF‐1 by 2.4 μg/L (p < 0.0001). Increments of 10 μg/L IGF‐1 were associated with a 0.85 g/L increase in Hb (P < 0.0001) and a 15% reduced risk of moderate‐to‐severe anemia (p = 0.001). IGF‐1 explained ~1/3 of the association between retinol and Hb, while only ~1/3 of the association between IGF‐1 and Hb was explained via iron status indicators. VA may improve Hb in pregnant women by increasing IGF‐1, which may act primarily by enhancing erythrocyte maturation rather than increasing iron availability for erythropoiesis.
The effect of iodine supplementation on status and cognition in iodine deficient young adults
Authors: Skeaff Sheila A , Fitzgerald Penelope CE , Redman Kahla , Ruffman Ted
Published: June 2021

Iodine is needed for brain development, which continues until the fifth decade of life, thus a lack of iodine in the diets of young adults could impair cognition. This was a randomized, double blind study of iodine deficient adults (n=205) aged 18–30 years who consumed 150 μg of potassium iodate or placebo daily for 32 wk. Subjects provided a urine and blood sample, and underwent cognitive tests from the Weschler Adult Intelligence Scale before and after supplementation. The median urinary iodine concentration (MUIC) at baseline was 65 μg/L indicating that the subjects were mildly iodine deficient (i.e. MUIC of 50–100 μg/L). Iodine supplementation significantly improved MUIC to 115 μg/L (p<0.001) such that subjects had adequate iodine status (i.e. MUIC >100 μg/L), while those in the placebo group remained iodine deficient (MUIC of 79 μg/L). The median serum thyroxine concentration of 97 nmol/L fell within the normal reference range at baseline and was not affected by supplementation (p=0.561). There was no effect of iodine supplementation on cognitive test scores that assessed perceptual reasoning including block design (p=0.385), matrix reasoning (p=0.364), and visual puzzles (p=0.675), or working memory including digit span backward (p=0.474) and letter‐number sequencing (p=0.408). This is the first study to suggest that mild iodine deficiency has no adverse consequences on cognition in young adults.
Improvements in perceptual and cognitive performance linked to baseline iron status and consumption of a double‐fortified salt
Authors: Wenger Michael , Murray-Kolb Laura , Hammons Julie , Venkatramanan Sudha , Haas Jere
Published: June 2021

Iron deficiency (ID) has numerous effects on individual functioning, including perception and cognition. Research has documented substantial deficits with ID and improvements with iron repletion. However, a weakness of this work has been its lack of specificity in measuring these changes. The present study considered the effects of ID and repletion in 248 female tea‐pickers of reproductive age (18–55 y) in West Bengal, India. Six measures of perceptual and cognitive performance‐‐‐simple reaction time, 2 measures of visual detection, 2 measures of attention, and recognition memory‐‐‐were selected for their ability to selectively examine perceptual and cognitive functioning relative to iron status. The measures were used in a randomized controlled double‐blind intervention involving salt double‐fortified with iodine and iron (DFS). Measures were taken before and after a 10‐month intervention. We previously reported substantial improvements as a function of experimental condition. We here link improvements in specific aspects of perceptual and cognitive performance to baseline iron status and total amount of DFS consumed. Support: Mathile Institute, Micronutrient Initiative, and NSF.
REDUCED FUNCTIONALITY OF RENIN‐ANGIOTENSIN‐ALDOSTERONE SYSTEM IN YOUNG RATS EXPOSED TO HIGH‐SALT DIET
Authors: Crestani Sandra , Garparotto Arquimedes , Marques Maria Consuelo Andrade , Sullivan Jennifer C. , Webb R. Clinton , da Silva Santos Jose Eduardo
Published: June 2021

High salt (HS) intake is putatively associated with increased incidence and prevalence of hypertension. We hypothesized that HS diet (NaCl at 2, 4 or 8%) given from weaning for 6 weeks would impair the renin‐angiotensin system (RAS). After treatment, animals were anesthetized and the effects of angiotensin I (AI) and II (AII) at 3, 10 and 30 ρmol/kg, or bradykinin (BK; 3, 10 and 30 nmol/kg) on mean arterial pressure (MAP) were evaluated. Blood samples were used to measure the activity of angiotensin converting enzyme (ACE), circulating aldosterone and AII levels. HS intake did not increase MAP, but the responsiveness to AI was increased around 40 and 80% in HS 4 and 8% groups. The plasmatic activity of ACE augmented from 80 ± 2 (control) to 91 ± 3 nmol/min/mlin HS 8% group, while BK‐induced hypotension was reduced. The effects of AII were also increased in HS 8% group. Despite the enhanced ACE activity and responsiveness to exogenous AII, rats exposed to HS intake presented reduced levels of plasmatic AII and aldosterone, suggesting that regulatory changes in RAS system may, at least in young rats, counteract the beginning of hypertension elicited by excessive salt ingestion.

Financial support: CAPES, CNPq and NIH.
Substance P‐induced increase in Brain Derived Neurotrophic Factor expression and secretion by intestinal smooth muscle is mediated by a rise in intracellular Ca2+
Authors: Alqudah Mohamamd Abdalkarim , Mahavadi Sunila , Srinivasa Karnam , Grider John
Published: June 2021

Background

We have previously shown that intestinal longitudinal smooth muscle cells express and secrete brain derived neurotrophic factor (BDNF) and addition of substance P (SP) to cultured smooth muscle cells induces further expression and secretion of BDNF above basal levels. It is not known, however, what cellular signaling pathways mediate SP‐induced expression and secretion of BDNF.

Aim

To identify the signaling pathways involved in BDNF synthesis and secretion by smooth muscle in response to SP.

Method

Cultured intestinal smooth muscle cells were treated with 10–100 nM SP for 24 hours in the presence and absence of 1,2 bis (o‐aminophenoxy)ethane‐N,N,N’,N’‐tetraacetic acid (BAPTA) to chelate intracellular Ca2+. BDNF protein expression and secretion were measured by in‐cell western and ELISA, and BDNF mRNA expression was measured by qRT‐PCR.

Results

The expression of BDNF protein was increased by 10–121% and BDNF secretion was increased by 50% by SP. Consistent with this, BDNF mRNA expression was increased by 161% by SP. Both BDNF protein and mRNA responses to SP were blocked by BAPTA.

Conclusion

SP stimulation of BDNF expression and secretion requires increased in intracellular Ca2+. The source of the intracellular Ca2+ increased remains to be determined. Supported by grants DK15564 and DK34153 from the National Institutes of Health.
Dysferlin maintains the integrity of transverse tubules and the junctional sarcoplasmic reticulum following contraction‐induced injury
Authors: Roche Joseph A , Resneck Wendy G , Mueller Amber L , Bloch Robert J
Published: June 2021

Background

Mutations in the DYSF gene that encodes the protein, dysferlin, lead to human muscular dystrophies known as dysferlinopathies.

Hypothesis

We tested the hypothesis that dysferlin is present at transverse tubules (TT) and that it helps stabilize TT and their interaction with the junctional sarcoplasmic reticulum (j‐SR) following contraction‐induced injury in vivo.

Methods and Results

Through improved tissue fixation and antigen unmasking, we found that most of the dysferlin in skeletal muscle is present in a myoplasmic reticulum that flanks Z‐disks in a pattern similar to markers of TT in healthy rat, mouse, and human skeletal muscle. Dysferlin is enriched in TT and SR fractions in sucrose gradients of rat muscle. Injury by large‐strain lengthening contractions increased the labeling intensity of myoplasmic dysferlin in wild type A/WySnJ mouse muscle. At 3hr post‐injury, dysferlin‐null A/J mouse muscle showed disrupted labeling for TT and j‐SR markers in ~75% fibers, whereas only ~20% showed disruption in wild type muscle. By 72hr post‐injury, ~20% and ~2% fibers were necrotic in A/J and A/WySnJ muscle, respectively, and the number of necrotic fibers was reduced 5‐fold in A/J mice treated with the L‐type calcium channel blocker, diltiazem.

Conclusion

Dysferlin plays an important role in protecting TT and the j‐SR from damage following contraction‐induced injury.
In vivo studies of motor nerve re‐growth following skeletal muscle damage by lengthening contractions
Authors: Vasilaki Aphrodite , Kayani Anna , Pearson Timothy , McArdle Anne , Jackson Malcolm
Published: June 2021

Very little is known about the pattern of changes in motor neurons that occur following skeletal muscle injury and during muscle regeneration during ageing in rodents or man. Our hypothesis is that physiologically relevant episodes of damage to muscle lead to a transient loss of innervation of the damaged muscle fibres with subsequent re‐growth of the terminal axons, interaction with the regenerating muscle fibres and formation of new neuromuscular junctions. Studies were undertaken in yellow fluorescent protein (YFP)‐H mice that only express YFP in neuronal cells. These mice provide a novel approach to assess the extent of motor neuron degeneration and regeneration. One extensor digitorum longus (EDL) muscle of adult YFP‐H mice was subjected to a protocol of 450 lengthening contractions involving a stretch to 120% of fibre length. The EDL muscle from the contralateral leg was used as control. This protocol produces an equivalent level of damage to 60–70% of the muscle fibres in muscles from adult and old mice. Maximal force generation by the EDL muscle in vivo was measured to examine the extent of functional denervation at 3, 14 and 28 days following damage. Mice were then killed, the EDL muscle was removed and the extent of loss and regrowth of peripheral motor neurons was examined by visualisation of labelled axons by fluorescence microscopy in the EDL. Supported by Research into Ageing, UK.
Contractile properties of mice deficient in dystrophin and the NADPH subunit p47phox
Authors: Engle Jeffrey A. , Rader Erik P. , Campbell Kevin P.
Published: June 2021

Duchenne muscular dystrophy is associated with a mutation in the gene encoding dystrophin. Dystrophin‐deficient muscle is highly susceptible to contraction‐induced injury. A report by N.P. Whitehead et al (2010) regarding mdx mice, described the efficacy of pharmacological inhibition of NADPH oxidase at decreasing contraction‐induced force deficits. This indicated that during lengthening contractions, NADPH oxidase may be a source of reactive oxygen species which contributes to the opening of stretch activated channels and the deleterious influx of extracellular calcium. To evaluate this proposal further and the role of p47phox – a subunit of NADPH oxidase – in particular, we tested the hypothesis that a stretch activated channel inhibitor (streptomycin), antioxidant (N‐acetylcysteine), calcium‐free buffer, and p47phox deficiency would decrease contraction‐induced injury for muscles of mdx mice. Mdx mice were crossed with p47phox null mice and isolated extensor digitorum longus muscles were exposed to the various conditions. Specific force was unaffected in all cases. Force deficits were reduced with the addition of streptomycin, N‐aceytcysteine, or calcium‐free buffer confirming earlier reports. A deficiency in p47phox diminished the increased muscle mass typical of mdx mice. However, lacking p47phox had no effect on force deficit. The results are consistent with reactive oxygen species and the influx of extracellular calcium via stretch activated channels mediating contraction‐induced injury in dystrophin deficient muscle. However, the findings indicate that the absence of p47phox does not reduce muscle dysfunction associated with dystrophin deficiency.
Aerobic Interval Training Improves Hemodynamic Response to Exercise by Enhancing Erythrocyte Rheological Function in Patients with Heart Failure
Authors: Chou Szu-Ling , Chen Rong-Rong , Wang Jong-Shyan
Published: June 2021

This study investigated how aerobic interval training (AIT) affects hemodynamic efficiency during exercise by modulating erythrocyte rheological characteristics in patients with heart failure (HF). Twenty patients with HF subjects performed the supervised hospital‐based AIT (3‐minute intervals at 40% and 80% VO2peak) for 30 minutes/day, 3 days/week for 12 weeks. Our results showed that AIT increased cardiac output and was accompanied by the decreases in systemic vascular resistance (SVR) and blood viscosity during exercise. Furthermore, this regimen significantly (i) reduced the levels of senescent (CD47−) and immature (CD71+) erythrocytes in blood, (ii) enhanced the ability to tolerance of erythrocytes to osmotic stress, (iii) depressed erythrocyte aggregability under flow condition, and (iv) increased the extent of erythrocyte deformation caused by shear stress. Moreover, improved erythrocyte rheological functions caused by AIT were associated with increased aerobic capacity and reduced SVR in the HF patients. Hence, we conclude that AIT enhances hemodynamic response to exercise, possibly by improving erythrocyte rheological function in patients with HF.
A Novel Role for Adipose Tissue in Exercise‐Induced Improvements in Glucose Homeostasis
Authors: Stanford Kristin I , Middelbeek Roeland J.W. , An Ding , Townsend Kristy L. , Markan Kathleen R. , Hitchcox Kristen M , Hellbach Katharina , Hirshman Michael F , Goodyear Laurie J
Published: June 2021

Exercise training improves whole body glucose homeostasis, effects largely attributed to adaptations to skeletal muscle; however, training also affects other tissues including adipose tissue. We used a transplantation model to test the hypothesis that adaptations to adipose tissue contribute to training‐induced improvements in glucose homeostasis. Mice were trained for 11 days or were sedentary, and subcutaneous (SubQ) or visceral adipose tissue was transplanted into the visceral cavity of sedentary recipients. Nine days after transplant, mice receiving SubQ adipose tissue from trained mice had improved glucose tolerance compared to mice transplanted with SubQ adipose tissue from sedentary mice and Sham‐operated mice. There was no effect of transplanting visceral adipose tissue. Transplantation of SubQ adipose tissue from trained mice for longer periods (12 wks) abolished the detrimental effects of high fat feeding on glucose homeostasis and obesity. Morphological and gene array analyses revealed numerous adaptations to trained SubQ adipose tissue, most notably, the development of metabolically active brown fatlike adipocytes within the SubQ adipose tissue. Exercise training results in adaptations to SubQ adipose tissue that result in profound metabolic improvements, demonstrating a previously unrecognized role for adipose tissue in the beneficial effects of exercise on glucose homeostasis.
Caloric restriction, aerobic exercise or a combination improves metabolic profiles following diet‐induced obesity
Authors: Glynn Erin L , An Jie , Wang Li-Ping , Ilkayeva Olga R , Stevens Robert D , Bain James R , Muehlbauer Michael J , Koves Timothy R , Summers Scott A , Muoio Deborah M , Newgard Christopher B
Published: June 2021

Diet‐induced obesity (DIO) is associated with several adverse metabolic changes including development of insulin resistance. Aerobic exercise (EX) &/or caloric restriction (CR) can improve many metabolic abnormalities. To examine independent & combined effects of EX & CR on global metabolism after DIO, male Wistar rats were fed a high fat diet (HF, 45%) ad‐libitum for 12 wk, then divided into 4 groups: continued HF diet (HF), 20% CR of HF (CR), ~20% caloric expenditure via EX (EX), or 10% CR + ~10% expenditure via EX (CR+EX). Controls were fed a low fat diet (LF) & samples were collected at 2 & 8 wk. Body weights in CR, EX & CR+EX were lower than LF or HF. Insulin sensitivity was impaired in HF compared to other groups. Preliminary metabolomics analyses show elevated plasma amino acids including leucine/isoleucine, methionine, phenylalanine & tyrosine, & acylcarnitine (AC) species C18:1 & C18:2 at 2 vs 8 wk in EX only. CR, EX or CR+EX often normalized liver AC toward LF values (e.g. C3, C16). DIO rats had lower respiratory exchange ratios (RER) & heat production vs LF, but values were higher in EX & CR+EX vs HF or CR. We conclude CR & EX induce similar improvement in insulin sensitivity but interventions including exercise result in additional changes in the metabolic profile compared to CR alone.

Supported by NIH grant PO1‐DK58398 and a grant from the Duke‐NUS, Singapore. E. Glynn was supported by the Jeane B. Kempner Scholar Award Fund.
Acetylcholine and insulin‐mediated vasodilation in feed arteries and arterioles of rat skeletal muscle of different fiber type composition
Authors: Padilla Jaume , Jenkins Nathan T , Martin Jeffrey S , Crissey Jacqueline M , Bender Shawn B , Rector R. Scott , Thyfault John P , Laughlin M. Harold
Published: June 2021

Obese, insulin resistant Otsuka Long Evans Tokushima Fatty rats (age 20 wk) were randomly assigned to sedentary (SED), endurance exercise training (EET), interval exercise training (IET), metformin, EET+MET, or IET+MET; and age‐matched Long‐ Evans Tokushima Otsuka rats were assigned to SED or MET. At sacrifice (age 30–32 wk), feed arteries from slow‐twitch soleus (SFA) and fast‐twitch gastrocnemius (GFA) muscles, and second order arterioles from red (G2aR) and white (G2aW) portions of the gastrocnemius muscle were isolated for in vitro assessment of vasomotor responses to acetylcholine (ACh, 10‐9‐10‐4 M), insulin (1–1000 μIU/mL), and sodium nitroprusside (SNP, 10‐9‐10‐4 M). Collapsing across all groups (total n=21), ACh and insulin‐mediated vasodilation in the SFA and G2aR were greater compared to the GFA and G2aW, respectively (all p<0.05). Conversely, SNP‐mediated vasodilation in the GFA was greater compared to the SFA (p<0.05), while G2aR and G2aW exhibited similar responses. Using a heterogeneous group of animals, these data suggest that ACh and insulin‐induced vasodilation is greater in skeletal muscle feed arteries and arterioles perfusing slow‐twitch oxidative muscle fibers than in feed arteries and arterioles perfusing fast‐twitch low oxidative muscle fibers. Support: NIH RO1HL036088, VA CDA‐2 IK2BX001299‐01, AHA 11POST5080002
Aerobic Interval Training Improves Muscular Oxygen Utilization and Depresses Vascular Endothelial Shedding in Sedentary Males
Authors: Tsai Hsing-Hua , Chen Ji-Ding , Wang Jong-Shyan
Published: June 2021

This study investigated the effects of aerobic interval (AIT) and moderate continuous (MCT) trainings on hemodynamics and oxygenation of skeletal muscles in men. Twenty sedentary males were randomized to perform either AIT (3‐minute intervals at 40% and 80% VO2peak, n=10) or MCT (sustained 60% VO2peak, n=10) for 30 minutes/day, 5 days/week for 5 weeks. A near‐infrared spectroscopy was employed to assess hemodynamics and oxygenation in vastus lateralis and gastrocnemius muscles. The level of circulating CD34−/KDR+/phosphatidylserine+ cells, which was defined as the shedding of endothelial cells from the vessel wall, was detected by three‐color flow cytometry. After the interventions, the AIT group exhibited a larger improvement in aerobic capacity than the NT group. Furthermore, the AIT regimen significantly (i) enhanced the ability of vastus lateralis muscle to extract oxygen during exercise, (ii) augmented the extents of hyperemic response and re‐oxygenation rate following ischemic stress in gastrocnemius muscle, and (iii) reduced the elevation of circulating CD34−/KDR+/phosphatidylserine+ cells caused by hypoxic stress. However, no significant changes in muscular hemodynamic function and vascular endothelial shedding were observed following 4‐week NT intervention. Hence, we conclude that the AIT regimen simultaneously improves muscular oxygenation and reduces the shedding of endothelial cells from the vasculature in sedentary males.
Hypoxic Exercise Training Improves Cardiac and Muscular Hemodynamics by Modulating Circulating Progenitor Cells in Sedentary Men
Authors: Wang Jong-Shyan , Lee Mei-Yi
Published: June 2021

This study investigated whether exercise regimens with/without hypoxia affect cardiac and muscular hemodynamics by modulating circulating progenitor cells (CPCs) and angiogenic factors. Forty sedentary males were randomly divided into hypoxic (HT, n=20) and normoxic (NT, n=20) training groups. The subjects were trained on a bicycle ergometer at 60% VO2max under 15% (HT) or 21% (NT) O2 conditions for 30 minutes daily, five days weekly for five weeks. After the interventions, the HT group exhibited a larger improvement in aerobic capacity than the NT group. Furthermore, the HT regimen (i) enhanced cardiac output (QH) and perfusion (QM)/oxygenation of vastus lateralis during exercise; (ii) increased the levels of circulating hematopoietic progenitor cell (HPC) and endothelial progenitor (EPC)/precursor (CEP) cells; (iii) promoted the proliferative capacity of these CPC subsets, and (iv) elevated plasma nitrite/nitrate, stromal cell‐derived factor‐1, matrix metalloproteinase‐9, and vascular endothelial growth factor‐A concentrations. Despite the lack of changes in QH and the number/proliferative capacity of HPC or CEP, the NT regimen elevated both QM and plasma nitrite/nitrate levels and suppressed the shedding of endothelial cells. We conclude that the HT regimen improves cardiac and muscular hemodynamic adaptations, possibly by promoting the mobilization/function of CPCs and the production of angiogenic factors.
Chronic administration of a thrombospondin‐1 mimetic: upsetting exercise capacity and the angiogenic balance in skeletal muscle
Authors: Audet Gerald N , Olenich Sara A , Stricker Janelle C , Roberts Kathleen A , Olfert I Mark
Published: June 2021

Skeletal muscle function is critical in exercise capacity. There is growing evidence that thrombospondin‐1 (TSP‐1), a potent anti‐angiogenic protein, is an important regulator of skeletal muscle function. We tested the hypothesis that chronic exposure to a TSP‐1 mimetic (ABT‐510) would decrease skeletal muscle capillarity and alter the balance between angiogenic proteins. Osmotic minipumps with ABT‐510 were implanted subcutaneously in the sub‐scapular region of C57/BLK6 mice for 14 days. This resulted in a 12% decrease in maximal running speed in the ABT‐510 treated group (P=0.028) with no significant change in the vehicle treated mice. When compared to the vehicle mice, the ABT‐510 group had a 13% decrease in capillarity in the gastrocnemius muscle (GA, P=0.055), 10% decrease in the plantaris muscle (PLT, P=0.051), and a 28% decrease in the soleus muscle (SOL, P<.001). ABT‐510 mice had decreased VEGF in both the GA and SOL muscles (GA; −30%, P=0.016; SOL; −38%, P=0.055), but no change in the PLT. There were no significant differences in endogenous TSP‐1 protein in the GA between groups. These data show that a TSP‐1 mimetic decreases whole body exercise and skeletal muscle capillarity, and alters the balance between VEGF and TSP‐1; and that chronic elevation of the TSP‐1 pathway can directly alter skeletal muscle structure and function.

Support: NIH 5T32‐HL090610, AHA 10BGIA3630002.
Genetics shift the angio‐adaptive balance in skeletal muscle of mice selected for high running capacity
Authors: Audet Gerald N , Meek Thomas H. , Garland Theodore , Olfert I Mark
Published: June 2021

Selective breeding for voluntary wheel running has resulted in mice with high inherited exercise capacity, which have been termed “mini muscle’ (MM) mice based on a small myofiber phenotype. We tested the hypothesis that an altered angiogenic expression profile would explain increased capillarity in MM compared to control (WT) mice. A subset of each group (N=5–8) were also acutely exercised for 1‐hr to test the angiogenic responsiveness to exercise. Gastrocnemius (GA) and plantaris (PLT) muscle capillarity were greater in MM vs WT (P<0.05). MM mice had 58% and 79% greater basal vascular endothelial growth factor (VEGF) protein in GA and PLT, respectively (P<0.05). Basal thrombospondin‐1 (TSP‐1) was unchanged in the GA, but 39% lower in PLT (P<0.05) of MM vs WT. In response to acute exercise, MM mice showed a 41% and 28% increase in VEGF in the GA and PLT, respectively (P<0.05). TSP‐1 protein was decreased by 90% in GA (P<0.05), but increased 50% in PLT (P<0.05). In contrast, there was no VEGF or TSP‐1 response to acute exercise in the GA of WT mice; however TSP‐1, but not VEGF, increased by 47% in the PLT of WT mice. An altered balance in basal VEGF and TSP‐1 correlates with greater capillarity in these selectively bred mice. These data suggest that basal expression and the response of key angiogenic regulators may be genetically influenced and account for the greater capillarity/enhanced exercise capacity in MM mice.
Upregulation of endogenous antioxidant defenses by Nrf2 activation does not blunt exercise‐induced mitochondrial biogenesis in rats
Authors: Reuland Danielle , Biela Laurie , Peelor Frederick , Drake Joshua , Miller Benjamin , Hamilton Karyn
Published: June 2021

It has been suggested that inhibition of reactive oxygen species signaling by exogenous antioxidants attenuates exercise‐induced mitochondrial biogenesis. Upregulation of endogenous antioxidants is a fundamentally different approach to maintaining redox balance and may avoid the blunting of exercise adaptations seen with exogenous antioxidants. Treatment with the phytochemicals in Protandim activates nuclear factor erythroid related factor‐2 (Nrf2) and upregulates antioxidant enzymes. We hypothesized that activation of Nrf2 would increase endogenous antioxidants without inhibition of exercise‐induced mitochondrial biogenesis. Sedentary or voluntary high‐volume wheel running rats were divided into control and Protandim‐fed groups. Long‐term mitochondrial protein fractional synthesis rates (FSR) were assessed using deuterium oxide labeling followed by GC‐MS analysis. Antioxidant enzymes HO‐1 and SOD‐1 were significantly greater in Protandim‐fed rats (p<0.05). Mitochondrial protein FSR in the soleus, plantaris, and liver was significantly greater in high volume runners compared to sedentary controls (p<0.05), and this increase was not attenuated by Protandim. Therefore, we conclude that increasing endogenous antioxidant defenses does not blunt exercise‐induced mitochondrial biogenesis and may provide a more effective approach to maintaining redox balance with exercise.
The Effect of Resistance Exercise Combined with Cholesterol Intake on Serum Lipid Profile in Elderly Men and Women
Authors: Chen Vincent C.W. , Lee Chang Woock , Lee Teak V. , Reichman Steven E.
Published: June 2021

The purpose of this study was to investigate the acute and training effects of resistance exercise (RE) on serum lipid profile with different levels of cholesterol intake. Thirty‐seven elderly men (M, N=15) and women (F, N=22) were randomly assigned to a high‐cholesterol, medium‐cholesterol or low‐cholesterol supplementation group and performed a RE training program for 12 weeks. Blood samples were obtained immediately before, after (acute) and 48‐hour after RE (prolonged). There were no significant differences on lipid profile between supplementation groups. Dietary cholesterol availability may alter RE induced cholesterol metabolism. Before and after training, HDL‐C, LDL‐C, TC and TG showed acute increases after RE and returned to normal 48 hours later, except for TG, which was decreased 48 hours after the last training section. Men showed greater acute RE changes than women for TC and TG before training, and HDL‐C, LDL‐C and TC after training. In conclusion, serum lipids were acutely increased by RE, TG use may be enhanced by RE training, and there may be sex‐specific differences in some of these effects.

Training Effect
Acute effect before training
Prolong ed effect before training
Acute effect after training
Prolong ed effect after training

HDL‐C

↑7.6%

↑9.2%  M > F

LDL‐C

↑4.2%

↑4.6%  M > F

Total Cholesterol (TC)

↑5.3%  M > F

↑6.2%  M > F

Triglyceride (TG)
↓2.1%  cov. MUFA
↑5.3%  M > F

↑6.9%
↓10.3%

HDL/LDL

↑3.5%
↑4.6%
↑4.9%
Exercise‐Induced Angiogenesis, Fiber Size and Muscle Mass Are Reduced in Skeletal Myofiber‐Specific VEGF Gene‐ Deleted Mice
Authors: Delavar Hamid , Tang Kechun , Wagner Peter D. , Breen Ellen C.
Published: June 2021

Exercise training stimulates angiogenesis in locomotor muscles. We hypothesize that VEGF expressed by skeletal myofibers is necessary for this angiogenic response and muscle hypertrophy. Using a conditional skeletal myofiber‐specific VEGF gene deletion mouse model (HSA‐Cre‐ERT2 X VEGFLoxP), VEGF levels are reduced by >80% in skeletal muscle of adult myofiber VEGF gene‐deleted mice (myoVEGF−/−) compared to control littermates (WT). 3 weeks after tamoxifen‐induced VEGF gene deletion, mice were exercise trained on a treadmill for 8 weeks (1 hr/d, 5d/wk). Capillary density, fiber size and muscle mass were measured in the gastrocnemius, soleus and plantaris. A selective decrease in the capillary/fiber ratio, mean fiber area, and muscle mass were found only in the gastrocnemius.

WT
myoVEGF−/−

Density (Cap./mm2)
Gastroc.
2.83 ± 0.54
1.87 ± 1.1*

Soleus
1.73 ± 0.20
1.39 ± 0.30

Plantaris
1.87 ± 0.23
1.85 ± 0.29

Mean Fiber Area (mm2)
Gastroc.
2830 ± 541
1870 ± 110*

Soleus
1725 ± 203
1387 ± 295

Plantaris
1871 ± 226
1850 ± 290

Cap/Fiber
Gastroc.
1.71 ± 0.18
1.03 ± .11**

Soleus
1.79 ± 0.15
1.65 ± 0.18

Plantaris
1.73 ± 0.22
1.39 ± 0.21

Muscle/Body weight (mg)
Gastroc.
5 ± 0.7
3 ± 0.5*

Soleus
0.6 ± 0.4
0.5 ± 0.4

Plantaris
2 ± 3
0.6 ± 0.1

Significant difference,

p<0.05,

p<0.01

These data suggest VEGF plays a role in regulating exercise‐induced angiogenesis and may be important for muscle hypertrophy and endurance adaptations to training.
Effects of physical exercise and taurine supplementation on cardio‐metabolic risk factors in high caloric‐fed rats
Authors: de Moraes Camila , Rosini Tiago Campos , de Freitas Ellen Cristini
Published: June 2021

To evaluate the effects of exercise sessions, three times a week, and taurine supplementation on blood concentration of glucose, triglycerides and TBARS. Twenty male Wistar rats were divided: sedentary (SD); sedentary taking taurine (SD+TAU); trained (TR) and trained taking taurine (TR+TAU). Exercise training and taurine supplementation (drinking water at 2%) started after four weeks of high caloric diet consumption and was carried out for further five weeks. Animals exercised at a treadmill (20 m/min), 60 min, 3 days/week. Insulin tolerance test (ITT) was done and KITT calculated. After an overnight fasting, rats were sacrificed and glucose, triglycerides, and TBARS concentrations were measured by commercial kits. Data were analyzed by two‐way ANOVA (p<0.05). Exercise protocol improved performance about 45% in booth trained groups. Exercise or taurine, per se, reduced triglycerides (40%,77% and 67% for SD+TAU, TR and TR+TAU, respectively) and augmented KITT (16%,20% and 26% SD+TAU, TR and TR+TAU). TBARS was reduced only in SD+TAU (33%) and TRD+TAU (29%). None differences were seen on body weight and in blood glucose. In conclusion, taurine supplementation, as physical exercise 3 days a week, improves metabolic profile in high caloric fed‐rats, except for oxidative stress biomarker. Financial support: FAPESP
Effect of exercise order on endocrine and metabolic responses to concurrent exercise
Authors: Aguirre Nicholas W. , Tan Jeremy G. , Coats Daniel R. , Spiering Barry A. , Brown Lee E. , Coburn Jared W. , Rubin Daniela A. , Judelson Daniel A.
Published: June 2021

Despite its popularity, few studies characterize the acute hormonal and metabolic responses to combined endurance and resistance exercise (concurrent exercise, CE). Since exercise order might influence training adaptations, elucidating these acute responses might contribute to optimizing program design. The purpose of this study was to examine the effects of CE order on endocrine and metabolic responses. Nine healthy, concurrently trained males (age = 22.7 ± 1.7 y; mass = 84.8 ± 11.9 kg; height = 176.1 ± 7.4 cm) performed two CE trials: resistance exercise (squat, bench press, lat pulldown: 60% 1‐RM, 4 sets × 10 reps, 90‐s rest intervals) followed by endurance exercise (RE‐EE) and EE (cycling: 80% ventilatory threshold for 30‐min) followed by RE (EE‐RE). Growth hormone, testosterone, cortisol, glucose, lactate (Lac) and free fatty acids were measured prior to CE, between exercise bouts, following CE, and 15, 30, and 60 minutes post‐CE. [Lac] was significantly greater at all post‐CE time points in EE‐RE (AUC = 909 ± 123 mmol•min/L) than RE‐EE (AUC = 777 ± 93 mmol•min/L). Plausibly, enhanced lactate metabolism during EE reduced [Lac] in RE‐EE. No differences were observed between trials for any other variable. Thus, differences in concurrent training adaptations predicated on CE order might not derive from humoral variations. Funding provided by California State University, Fullerton.
Previous day's exercise does not affect indicators of physiological stress measured during practice in male collegiate soccer players
Authors: Dautermann Valerie Mae , Johnson Kathryn M.S.
Published: June 2021

Exercise, including participation in athletics, induces physiological stress. To determine if previous bouts of exercise alter physiological stress induced by a strenuous soccer practice, healthy male collegiate soccer players (n = 14) participated in two identical practices, one following a game day and the other after a rest day. After a 30‐minute baseline period, subjects participated in a 90‐minute practice, which included warm‐ups, ball drills, sprints, and scrimmage. Salivary cortisol levels were measured twice during baseline, thrice during practice, and once after practice. Blood pressure (BP) and heart rate (HR) were measured in a subset of participants (n =6). Fifty‐meter timed sprints, used to compare athletic performance of participants between practices, were the same on both days (7.28 ± 0.13 and 7.26 ± 0.17 sec, after rest and after game, respectively). Although exercise induced an increase in all measured parameters, there was no difference in salivary cortisol levels (0.252 ± 0.023 and 0.235 ± 0.016 μg/dL), HR (107 ± 5 and 99 ± 3 beats/min), or diastolic BP (80 ± 1 and 77 ± 2 mmHg) between practices; however, systolic BP was significantly different (141 ± 5 and 133 ± 4 mmHg; p < 0.01). Therefore, the physiological stress induced during a practice is not different the day after a game compared to the day after a rest day. V. Dautermann was supported by the Beloit College Biomedical Scholars Program.
Bone metabolic markers and BMD after 10 weeks upper‐body resistance training in premenopausal women
Authors: Quezada Lorena , Liang Michael T.C. , Sokmen Bulent , Spalding Thomas W
Published: June 2021

The aim of this study was to determine the effects of a 10‐week upper body resistance training (UBRT) on bone turnover markers (BTM) and site‐specific BMD in the wrist and distal ½ of the ulna and radius in untrained healthy premenopausal women. Twenty‐eight healthy subjects (age=22.1±1.8 yr) were randomly assigned to UBRT (UT, n = 12) or no training control (CON, n = 8) group. The following outcome variables were measured before and after 10 weeks of resistance training: 1) bone formation biomarker, osteocalcin (OC), and bone resorption biomarker, tartrate‐resistant acid phosphatase isoform 5b (TRACP5b), 2) BMD in the wrist, distal ½ of the ulna and radius, and heel, 3) isokinetic strength of the elbow and knee extensors and flexors, 4) arm extensors and flexors, and 5) maximal number of push‐ups. No significant group differences were observed for BTM (mean±SE, OC: 14.5±0.8 vs. 14.7±0.4 ng/ml and TRACP5b: 2.69±0.36 vs. 2.60±0.37 U/L, both p>0.05), and wrist BMD (0.487±0.01 vs. 0.444±0.01 g/cm2, p>0.05). Compared to baseline values, 1RM chest press and lateral pull‐downs increased 24% and 16%, respectively, and number of push‐ups increased 111% (all p<0.05) in the UT, not the CON. We conclude that muscular strength can be induced with a 10‐week musculoskeletal loading using resistance training, but not in bone metabolic markers and BMD in the wrist and distal ½ of the ulna and radius in untrained premenopausal women.
Inter‐participant variability in circulating cortisol and nuclear hsp90 concentrations following short‐term aerobic activity
Authors: Biette Kelly , Anderson Michelle E. , Petlow Angela M. , Murphy Patrick J. M.
Published: June 2021

Salivary cortisol (CORT) concentrations were measured in healthy volunteers (n=66) before and after a 7.5‐minute guided aerobic exercise activity in order to determine fluctuations in endogenous CORT levels and exercise‐induced CORT response. Single nucleotide polymorphisms (SNPs) within DNA encoding the glucocorticoid receptor (GR) cortisol binding domain and differences in CORT‐associated proteins (i.e. GR and hsp90) were measured in white blood cell samples from a subset of participants (n=19). Pre‐ to 20 minute post‐activity CORT levels ranged from a 60% decrease to >300% increase. Interestingly, the group of participants whose CORT levels exhibited the greatest decrease had significantly higher pre‐activity CORT levels when compared to all other participant groups. No correlations were detected between CORT variability and collected demographic data. Participants showing the greatest pre‐ to post‐activity CORT decrease and those showing highest pre‐activity CORT levels had significantly elevated concentrations of nuclear hsp90 compared to other participant groups. One SNP was detected, occurring in 3 of the 19 participants and representing a synonymous AAT>AAC polymorphism at GR protein residue 766. These data demonstrate inter‐person differences in baseline CORT levels, variability in CORT response, and nuclear hsp90 concentrations are readily detected and potentially interrelated.
Anemia‐declined Functional Capacity Is Associated with Impaired Erythrocyte Rheological Function in Patients with Heart Failure
Authors: Chiang Cheng-Ling , Chou Szu-Ling , Chang Shu-Yuan , Wang Jong-Shyan
Published: June 2021

Anemia is a common co‐morbidity in patients in heart failure (HF), which develops further deconditioning and consequently vicious cycle of cardiovascular disorders. Whether anemia influences the rheological characteristics and leads to exercise intolerance in the HF patients remains unclear. This study investigated the relationship between erythrocyte rheological functions and function capacity in the HF patients with anemia. According to the WHO criteria, eighty‐eight CHF patients were divided into normal (N‐A, n=47), light anemic (L‐A, n=21), and moderate‐several anemic (MS‐An, n=20) groups. Our results revealed that the MS‐An group had (i) smaller VO2peak and oxygen uptake efficiency slope and greater VE‐VO2 slope, (ii) higher levels of senescent (CD47−) and immature (CD71+) erythrocytes in blood, (iii) less the ability to tolerance of erythrocytes to osmotic stress, (iv) larger erythrocyte aggregability that was accompanied by elevated blood viscosity, and (v) lower the degree of erythrocyte deformation caused by shear stress, compared to those of both N‐A and L‐A groups. Moreover, the extents of impaired erythrocyte rheological functions were associated with the decline of aerobic capacity in the HF patients. We conclude that anemia limits the delivery of oxygen to tissues by impairing erythrocyte rheological function, thereby reducing functional capacity in patients with HF.
Prolonged endurance exercise decreases fiber loss and fiber atrophy in aged male rats
Authors: Barton Gregory P , McKiernan Susan H , Akins Tiffany , Hoffman Marie , Aiken Erik , Martin-Koob Joanne , Aiken Judd , Diffee Gary
Published: June 2021

Sarcopenia is the age‐related loss of muscle mass and function. Effects of long‐term exercise training on sarcopenia have not been well defined. In this study we assessed skeletal muscle adaptations to prolonged exercise training in rats from late‐middle age to old age. Male rats, 24 mo of age, trained on a treadmill at three levels of intensity: high (HI: 13m/min, 5% incline for 30 min, 5 days per week), moderate (MI: 13m/min, 0% incline for 30 min, 5 days per week), minimally active (MA: 5m/min, for 5 min, 2 days per week) and a sedentary group (S). Rats ran for one year until the rats were age 36 months. The rectus femoris (RF) muscle from 24‐month Controls (C), and 36‐month HI, MI, MA, and S. The RF was weighed, bisected, frozen, sectioned and stained with hematoxylin and eosin. Digital images of RF cross‐sections were used to determine muscle area, fiber number and fiber diameter. Aging significantly reduced muscle mass, muscle area, fiber number and fiber diameter, (24‐month C compared to any of the 36‐month old S, MA, MI or HI). Among the 36‐mo. rats (HI, MI, MA, and S), no differences were observed in muscle mass or muscle area. However, there was a significant increase in fiber number and fiber diameter in all exercise groups (HI, MI, and MA) compared to S. These results indicate that any level of exercise, even minimal levels of activity is capable of decreasing the effects of sarcopenia in aging rats.

Supported by NIH AG 030423.