The Effects of Anabolic-Androgenic Steroids on Gene Expression in Skeletal Muscle: A Systematic Review.

Anabolic-androgenic steroids (AAS) act via androgen receptor (AR) interaction to induce muscle protein synthesis. This process is achieved via altered gene expression via the Notch, Wnt, and Numb pathways and their interactions at the AR, manifesting in key skeletal muscle (SM) phenotypes such as morphology, ion conductance, and functionality. This review aims to report on the effects of AAS administration on gene expression in SM. Peer-reviewed empirical studies evaluating AAS administration on SM phenotypes and gene expression were considered for inclusion. The following databases were searched using a data range of Jan 2000-November 2020: MEDLINE Complete, Academic Search Complete, APA PsycInfo, SPORTDiscus, CINAHL Plus, Cochrane Central Register of Controlled Trials, Rehabilitation & Sports Medicine Source, GreenFILE, and APA PsycArticles. Potential risks of bias were assessed via a modified PEDro Scale. Twenty-nine peer-reviewed titles were included. All studies consisted of either human or rodent subjects and included an AAS dosing protocol, investigated SM phenotypes, and measured gene expression as an outcome variable. Studies investigated the effects of eight AAS compounds across a total of 88 different genes in SM. The most commonly identified genes increased by AAS were IGF, MYOG, and MyoD. There was a general lack of standardized dosing and AAS variety. Future studies should attempt to incorporate multiple AAS compounds and their effects on key SM gene expression.

Acute cardiovascular responses to unilateral bicep curls with blood flow restriction.

A consensus on the acute cardiovascular responses to low intensity (LI) resistance exercise (RE) combined with blood flow restriction (BFR) has not yet been reached. This study was designed to compare acute cardiovascular responses to a single bout of LIRE, high intensity (HI) RE, and LIRE with BFR in physically active young males. Participants completed 3 RE sessions in random order, where each session consists of 4 sets of unilateral dumbbell bicep curls. Cardiovascular hemodynamics were measured at baseline and right after each set of RE. Aortic augmentation index (AIx) was significantly higher after set 2,3,4 of RE in LI + BFR session compared to LI session (P < 0.05). Brachial systolic blood pressure (SBP), heart rate (HR), brachial rate pressure product (RPP), and central RPP responses did not differ between LI and LI + BFR sessions (P > 0.05). HI session had a higher central SBP, brachial RPP, central RPP, and aortic AIx compared to LI session after each set of RE (P < 0.05), but not brachial SBP (P > 0.05). Taken together, this study showed that LIRE combined with BFR acutely augmented aortic stiffness, as also observed in HI session, but myocardial oxygen consumption was only higher in HI session when compared to LI session. Thus, although BFR did not exaggerate cardiovascular responses nor cause extra myocardial oxygen consumption, it should be prescribed with caution when control of acute aortic stiffening is necessary during RE.

Physical Activity and the Acute Hemodynamic Response to ACE Inhibition in Hypertension.

Introduction. Physical activity (PA) can reduce blood pressure (BP) in hypertensives through possibly interacting with the renin-angiotensin-aldosterone system (RAAS). We conducted a nested-cohort analysis to determine if self-reported PA was associated with BP responsiveness to acute angiotensin converting enzyme inhibition (ACEi). Methods. Data were extracted from the HyperPATH dataset, a cohort designed to identify mechanisms of cardiometabolic risk. Hypertensives that completed a self-assessed PA questionnaire, hormonal assessments (aldosterone [ALDO]), and BP to a single dose of an ACEi (captopril, 25 mg) were included. All participants (n = 144) were studied on a controlled diet for 7 days. PA was recorded as no PA, or little, moderate, or high amounts of exercise. Analyses were adjusted for age, sex, race, and body mass index. Results. Individuals who reported high amounts of PA displayed a greater BP lowering effect from ACEi compared to those who reported moderate (-14.8 ± 8.1 vs -8.4 ± 9.9 mm Hg, P < .01) or no additional PA (-14.8 ± 8.1 vs -2.6 ± 9.9 mm Hg, P < .001). Exploratory analyses indicated high amounts of PA were associated with a reduced heart rate (54 ± 8 vs 66 ± 10 bpm, P < .001) and blunted ALDO (ß = 0.44, 95% confidence interval = 0.19-0.70). Conclusions. Higher self-reported PA was associated with an augmented BP lowering effect to acute ACEi in hypertensive patients.

Biological sex modifies aldosterone's secretion at a cellular level.

Inconsistencies have been reported on the effect of sex on aldosterone (ALDO) levels leading to clinical confusion. The reasons for these inconsistencies are uncertain but include estrogen and/or its receptor modulating target gene responses to mineralocorticoid receptor activation and ALDO secretagogues' levels. This study's goal was to determine whether ALDO's biosynthesis also differed by sex. Two approaches were used. First, plasma renin activity and aldosterone were measured in rats. Both were significantly higher in males. Secondly, using rat zona glomerulosa (ZG) cells, we assessed three ex vivo areas: (1) activity/levels of early steps in ALDO's biosynthesis (StAR and CYP11A1); (2) activity/levels of a late step (CYP11B2); and (3) the status of the mineralocorticoid receptor (MR)-mediated, ultrashort feedback loop. Females had higher expression of CYP11A1 and StAR and increased CYP11A1 activity (increased pregnenolone/corticosterone levels) but did not differ in CYP11B2 expression or activity (ALDO levels). Activating the ZG's MR (thereby activating the ultrashort feedback loop) reduced CYP11B2's activity similarly in both sexes. Exvivo, these molecular effects were accompanied, in females, by lower ALDO basally but higher ALDO with angiotensin II stimulation. In conclusion, we documented that not only was there a sex-mediated difference in the activity of ALDO's biosynthesis but also these differences at the molecular level help explain the variable reports on ALDO's circulating levels. Basally, both in vivo and ex vivo, males had higher ALDO levels, likely secondary to higher ALDO secretagogue levels. However, in response to acute stimulation, ALDO levels are higher in females because of the greater levels and/or activity of their StAR/CYP11A1.

Isometric Exercise Training: A Review of Hypothesized Mechanisms and Protocol Application in Persons with Hypertension.

According to the American Heart Association 116.4 million, or 46% of US adults are estimated to have hypertension. Although, traditional moderate intensity aerobic exercise training is associated with reducing blood pressure by 5-8 mmHg, barriers to this modality of exercise training exist. Thus, the purpose of this review is to evaluate the mechanisms and incorporation of isometric exercise training (IET) as an adjunctive mode of exercise in a population with HTN. Based upon the articles reviewed from the years 2000-2020 which incorporated IET and provided clear protocols lasting 4 or more weeks, meaningful reductions in blood pressure occurred following IET (SBP, -9.7 ± 3.3 mmHg; DBP, -4.8 ± 2.6 mmHg) which support the need to increase adoption of this exercise form into practice to help treat hypertension. Specifically, an IET program of 12-20 minutes per day, 3 times per week, could improve blood pressure reduction in those with hypertension. IET has the potential to produce significant and clinically meaningful blood pressure reductions and could serve as an adjunctive exercise modality alongside the established exercise prescription for those with hypertension.

mTORC1 Deficiency Modifies Volume Homeostatic Responses to Dietary Sodium in a Sex-Specific Manner.

The mechanistic target of the rapamycin (mTOR) pathway plays a role in features common to both excess salt/aldosterone and cardiovascular/renal diseases. Dietary sodium can upregulate mTORC1 signaling in cardiac and renal tissue, and the inhibition of mTOR can prevent aldosterone-associated, salt-induced hypertension. The impact of sex and age on mTOR's role in volume homeostasis and the regulation of aldosterone secretion is largely unknown. We hypothesize that both age and sex modify mTOR's interaction with volume homeostatic mechanisms. The activity of 3 volume homeostatic mechanisms-cardiovascular, renal, and hormonal (aldosterone [sodium retaining] and brain natriuretic peptide [BNP; sodium losing])-were assessed in mTORC1 deficient (Raptor+/-) and wild-type male and female littermates at 2 different ages. The mice were volume stressed by being given a liberal salt (LibS) diet. Raptor+/-mice of both sexes when they aged: (1) reduced their blood pressure, (2) increased left ventricular internal diameter during diastole, (3) decreased renal blood flow, and (4) increased mineralocorticoid receptor expression. Aldosterone levels did not differ by sex in young Raptor+/- mice. However, as they aged, compared to their littermates, aldosterone decreased in males but increased in females. Finally, given the level of Na+ intake, BNP was inappropriately suppressed, but only in Raptor+/- males. These data indicate that Raptor+/- mice, when stressed with a LibS diet, display inappropriate volume homeostatic responses, particularly with aging, and the mechanisms altered, differing by sex.

Sex-specific differences in endoplasmic reticulum aminopeptidase 1 modulation influence blood pressure and renin-angiotensin system responses.

Salt sensitivity of blood pressure (SSBP) and hypertension are common, but the underlying mechanisms remain unclear. Endoplasmic reticulum aminopeptidase 1 (ERAP1) degrades angiotensin II (ANGII). We hypothesized that decreasing ERAP1 increases BP via ANGII-mediated effects on aldosterone (ALDO) production and/or renovascular function. Compared with WT littermate mice, ERAP1-deficient (ERAP1+/-) mice had increased tissue ANGII, systolic and diastolic BP, and SSBP, indicating that ERAP1 deficiency leads to volume expansion. However, the mechanisms underlying the volume expansion differed according to sex. Male ERAP1+/- mice had increased ALDO levels and normal renovascular responses to volume expansion (decreased resistive and pulsatility indices and increased glomerular volume). In contrast, female ERAP1+/- mice had normal ALDO levels but lacked normal renovascular responses. In humans, ERAP1 rs30187, a loss-of-function gene variant that reduces ANGII degradation in vitro, is associated with hypertension. In our cohort from the Hypertensive Pathotype (HyperPATH) Consortium, there was a significant dose-response association between rs30187 risk alleles and systolic and diastolic BP as well as renal plasma flow in men, but not in women. Thus, lowering ERAP1 led to volume expansion and increased BP. In males, the volume expansion was due to elevated ALDO with normal renovascular function, whereas in females the volume expansion was due to impaired renovascular function with normal ALDO levels.

Interactions of the DASH Diet with the Renin-Angiotensin-Aldosterone System.

BACKGROUND: The Dietary Approaches to Stop Hypertension (DASH) diet is widely recommended to lower blood pressure, but its mechanisms of action are unclear. Lines of evidence suggest an interaction with the renin-angiotensin-aldosterone system (RAAS). OBJECTIVE: We conducted a randomized, controlled, cross-over feeding trial to test RAAS-related mechanisms underlying the DASH diet in patients with isolated systolic hypertension. METHODS: Participants entered a 1-wk run-in period on a control (CON) diet and then consumed the DASH or CON diets for 4 wk each in randomized sequence. Calorie content was controlled to maintain weight, and sodium intake was set at 3 g daily. After each diet, participants had hormonal and hemodynamic assessments obtained at baseline, in response to RAAS inhibition with captopril (CAP) 25 mg, and to graded angiotensin II (AngII) infusions (1 ng/kg and 3 ng/kg × 45 min). Primary outcomes were mean arterial pressure (MAP) and renal blood flow (RBF), and secondary outcomes were diastolic function, pulse wave velocity (PWV), plasma renin activity (PRA), and aldosterone (ALDO) responses by diet. RESULTS: In total, 44 (19 female) participants completed the study. DASH + CAP significantly lowered MAP compared with CON + CAP (83 ± 11 mmHg compared with 88 ± 14 mmHg, P <0.01). RBF was increased with DASH + CAP compared with CON + CAP (486 ± 149 cc/min compared with 451 ± 171 cc/min, P <0.001). Study diet did not change PWV but CAP reduced diastolic function on the DASH diet (P <0.05). DASH + CAP significantly increased PRA compared with CON + CAP (1.52 ± 1.78 ng/mL/min compared with 0.89 ± 1.17 ng/mL/min; P <0.001). ALDO sensitivity to AngII infusion was greater with DASH when compared to CON (17.4 ± 7.7 ng/mL compared with 13.8 ± 6.2 ng/dL, P <0.05) as was DASH + CAP compared with CON + CAP (15.1 ± 5.3 ng/dL compared with 13.1 ± 5.9 ng/mL, P <0.05). CONCLUSIONS: The DASH diet interacts with the RAAS resulting in vascular and hormonal responses similar to a natriuretic effect, which appears to augment the hypotensive effect of angiotensin-converting enzyme (ACE) inhibition in individuals with isolated systolic hypertension. This trial was registered at clinicaltrials.gov as NCT00123006.

Comparing the Changes in Blood Pressure After Acute Exposure to Tai Chi and Walking.

Hypertension is a major health concern throughout the United States and is a major cause of cardiovascular disease. The purpose of this study was to compare the responses of Tai Chi and walking on measures of central and peripheral cardiac mechanisms when controlling for exercise intensity. Fifteen hypertensive subjects (2 males, 13 females; age = 20.7 ± 3.77 years; body fat = 24.26 ± 10.27%) participated in Tai Chi (TC) and walking (WK) for 30 minutes on non-consecutive days. Central systolic (CSBP) and diastolic blood pressure (CDBP), augmentation index (Alx), pulse pressure (PP), heart rate (HR), and brachial systolic (BSBP) and diastolic blood pressure (BDBP) were measured prior to exercise and following exercise every 10 minutes for a total of 60 minutes in a seated position. There were no significant differences between the two exercise forms. CSBP decreased 10 minutes after exercise in both exercise types (TC = 6.63 ± 3.258 mmHG; WK = 7 ± 4.144 mmHG p < 0.05), and 40 minutes after exercise in both exercise types (TC = 6.07 ± 3.33 mmHG; WK = 8.2 ± 3.15 mmHG, p < 0.05) compared to the initial measurement. BSBP also decreased in both exercise forms following 10 min of rest (TC = 6.99 ± 3.776 mmHG; WK = 8.8 ± 3.20 mmHG p = 0.05), and 40 min (TC = 8.46 ± 3.07 mmHG; WK = 8.87 ± 3.87 mmHG, p < 0.05) when compared to the initial resting measurement. Central aortic pressure exhibits a post exercise hypotensive (PEH) effect similar to that of peripheral blood pressure. Both Tai Chi and walking elicited similar PEH effects on systolic blood pressure in hypertensive individuals.