State of Knowledge on Molecular Adaptations to Exercise in Humans: Historical Perspectives and Future Directions.

For centuries, regular exercise has been acknowledged as a potent stimulus to promote, maintain, and restore healthy functioning of nearly every physiological system of the human body. With advancing understanding of the complexity of human physiology, continually evolving methodological possibilities, and an increasingly dire public health situation, the study of exercise as a preventative or therapeutic treatment has never been more interdisciplinary, or more impactful. During the early stages of the NIH Common Fund Molecular Transducers of Physical Activity Consortium (MoTrPAC) Initiative, the field is well-positioned to build substantially upon the existing understanding of the mechanisms underlying benefits associated with exercise. Thus, we present a comprehensive body of the knowledge detailing the current literature basis surrounding the molecular adaptations to exercise in humans to provide a view of the state of the field at this critical juncture, as well as a resource for scientists bringing external expertise to the field of exercise physiology. In reviewing current literature related to molecular and cellular processes underlying exercise-induced benefits and adaptations, we also draw attention to existing knowledge gaps warranting continued research effort. © 2021 American Physiological Society. Compr Physiol 12:3193-3279, 2022.

Lipopolysaccharide binding protein is associated with CVD risk in older adults.

BACKGROUND: Intestinal (i.e., "gut") permeability may be related to cardiovascular disease (CVD) risk, but biomarkers for gut permeability are limited and associations with CVD risk are unknown-particularly among older adults. AIMS: This cross-sectional study aimed to determine if serum biomarkers related to gut permeability [intestinal fatty acid-binding protein (iFABP)] and bacterial toxin clearing [cluster of differentiation 14 (CD14), lipopolysaccharide binding protein (LBP)] are associated with CVD risk among older adults. METHODS: Older adults (n = 74, 69.6 ± 6.5-years-old) were stratified by CVD risk category. One-way ANOVAs determined differences in each biomarker by risk category, and associations with risk score were evaluated with Pearson correlations. RESULTS: LBP (p = 0.007), but not iFABP and CD14, was significantly different between CVD risk categories. Post-hoc tests indicated LBP was higher in moderate risk and high-moderate risk compared to the high risk category (p < 0.005). Evaluation of LBP and individual components in the risk score demonstrated a moderate, negative correlation of LBP with age and systolic blood pressure (r = - 0.335 and r = - 0.297) and a small positive correlation between LBP and total cholesterol and LDL cholesterol (r = 0.204 and r = 0.220). DISCUSSION/CONCLUSION: Lower risk for CVD was associated with higher circulating concentrations of LBP, lower iFABP, and lower systemic inflammation in older adults. Further, there were small positive relationships between total and LDL cholesterol and circulating levels of LBP. These data suggest LBP may be a key component in reducing CVD risk in older adults.

Resveratrol and exercise combined to treat functional limitations in late life: A pilot randomized controlled trial.

PURPOSE: To evaluate the safety and feasibility of combining exercise (EX) and resveratrol to treat older adults with physical function limitations. METHODS: Three-arm, two-site pilot randomized, controlled trial (RCT) for community-dwelling adults (N = 60), 71.8 ± 6.3 years of age with functional limitations. Participants were randomized to receive either 12 weeks of (1) EX + placebo [EX0], (2) EX + 500 mg/day resveratrol [EX500], or (3) EX + 1000 mg/day resveratrol [EX1000]. EX consisted of two sessions a week for 12 weeks of center-based walking and whole-body resistance training. Safety was assessed through adverse events and feasibility through exercise session and supplement (placebo, or resveratrol) protocol adherence. Outcome measures included a battery of indices of physical function as well as skeletal muscle mitchondrial function. Data were adjusted for age and gender using the Intent-To-Treat approach. RESULTS: Adverse event frequency and type were similar between groups (n = 8 EX0, n = 12 EX500, and n = 7 EX1000). Overall, 85% of participants met the supplement adherence via pill counts while 82% met the exercise session adherence. Adjusted within group mean differences (95% confidence interval) from week 0 to 12 for gait speed ranged from -0.04 (EX0: -0.1, 0.03) m/s to 0.04 (EX1000: -0.02, 0.11) and the six-minute walk test mean differences were 9.45 (EX0: -9.02, 27.7), 22.9 (EX500: 4.18, 41.6), and 33.1 (EX1000: 13.8, 52.4) meters. Unadjusted mean differences for citrate synthase were -0.80 (EX0: -15.45, 13.84), -1.38 (EX500: -12.16, 9.39), and 7.75 (EX1000: -4.68, 20.18) mU/mg. COX activity mean within group changes ranged from -0.05 (EX0) to 0.06 (EX500) k/s/mg. Additional outcomes are detailed in the text. CONCLUSION: The pilot RCT indicated that combined EX + resveratrol was safe and feasible for older adults with functional limitations and may improve skeletal muscle mitochondrial function and mobility-related indices of physical function. A larger trial appears warranted and is needed to formally test these hypotheses.

Angiotensin (1-7) delivered orally via probiotic, but not subcutaneously, benefits the gut-brain axis in older rats.

To (1) investigate the efficacy of multiple doses of an orally delivered probiotic bacteria Lactobacillus paracasei (LP) modified to express angiotensin (1-7) (LP-A) in altering physiologic parameters relevant to the gut-brain axis in older rats and to (2) compare this strategy with subcutaneous delivery of synthetic Ang(1-7) peptide on circulating Ang(1-7) concentrations and these gut-brain axis parameters. Male 24-month-old F344BN rats received oral gavage of LP-A, or subcutaneous injection of Ang(1-7) for 0×, 1×, 3×, or 7×/week over 4 weeks. Circulating RAS analytes, inflammatory cytokines, and tryptophan and its downstream metabolites were measured by ELISA, electrochemiluminescence, and LC-MS respectively. Microbiome taxonomic analysis of fecal samples was performed via 16S-based PCR. Inflammatory and tryptophan-related mRNA expression was measured in colon and pre-frontal cortex. All dosing regimens of LP-A induced beneficial changes in fecal microbiome including overall microbiota community structure and α-diversity, while the 3×/week also significantly increased expression of the anti-inflammatory species Akkermansia muciniphila. The 3×/week also increased serum serotonin and the neuroprotective analyte 2-picolinic acid. In the colon, LP-A increased quinolinate phosphoribosyltransferase expression (1×/week) and increased kynurenine aminotransferase II (1× and 3×/week) mRNA expression. LP-A also significantly reduced neuro-inflammatory gene expression in the pre-frontal cortex (3×/week: COX2, IL-1ß, and TNFα; 7×/week: COX2 and IL-1ß). Subcutaneous delivery of Ang(1-7) increased circulating Ang(1-7) and reduced angiotensin II, but most gut-brain parameters were unchanged in response. Oral-but not subcutaneous-Ang(1-7) altered physiologic parameters related to gut-brain axis, with the most effects observed in 3×/week oral dosing regimen in older rats.

The Gut Microbiome as a Therapeutic Target for Cognitive Impairment.

Declining cognitive functions in older individuals have enormous emotional, clinical, and public health consequences. Thus, therapeutics for preserving function and keeping older adults living independently are imperative. Aging is associated dysbiosis, defined as a loss of number and diversity in gut microbiota, which has been linked with various aspects of cognitive functions. Therefore, the gut microbiome has the potential to be an important therapeutic target for symptoms of cognitive impairment. In this review, we summarize the current literature regarding the potential for gut-targeted therapeutic strategies for prevention/treatment of the symptoms of cognitive impairment. Specifically, we discuss four primary therapeutic strategies: wild-type and genetically modified probiotics, fecal microbiota transplantation, physical exercise, and high-fiber diets and specifically link these therapies to reducing inflammation. These strategies may hold promise as treatment paradigm symptoms related to cognitive impairment.

Wearable Technology To Reduce Sedentary Behavior And CVD Risk In Older Adults: A Pilot Randomized Clinical Trial.

BACKGROUND: Physical exercise is associated with decreased cardiovascular disease (CVD) risk, but recent large-scale trials suggest that exercise alone is insufficient to reduce CVD events in high-risk older adults. PURPOSE: This pilot randomized clinical trial aimed to collect critical data on feasibility, safety, and protocol integrity necessary to design a fully powered randomized controlled trial (RCT) and evaluate the impact of combining structured exercise with an intervention designed to enhance non-exercise physical activity (EX+NEPA) compared to EX alone. METHODS: Forty participants aged ≥60 years with moderate-to-high risk of coronary heart disease events were randomly assigned to either the EX+NEPA or EX groups and followed for 20 weeks. Both groups underwent a twice-weekly, 8-week center-based exercise intervention with aerobic and resistance exercises. EX+NEPA group also received a wearable activity tracking device along with behavioral monitoring and feedback throughout the study. Study outcomes were evaluated at 8 and 20 weeks. RESULTS: Data are presented as adjusted mean change of the differences over time with 95% confidence intervals at 20 weeks. Relative to EX, the change in steps/day at 20 weeks was 1994 (-40.27, 4028) higher for EX+NEPA. For sedentary time at close-out, the EX+NEPA group was -6.8 (-45.2, 31.6) min/day relative to EX. The between-group differences for systolic and diastolic blood pressure were -9.9 (-19.6, -0.3) and -1.8 (-6.9, 3.3) mmHg, respectively. CONCLUSION: The addition of wearable technology intervention appeared to positively influence daily activity patterns and changes in blood pressure - potentially improving risk factors for CVD. A fully powered randomized trial is needed to ultimately test this hypothesis.

Age-related deficits in bilateral motor synergies and force coordination.

BACKGROUND: Ageing may cause impairments in executing bilateral movement control. This study investigated age-related changes in interlimb force coordination across multiple trials by quantifying bilateral motor synergies based on the uncontrolled manifold hypothesis. Participants completed the trials with and without visual feedback. METHODS: Twenty healthy individuals (10 older adults and 10 young adults) performed 12 isometric force control trials for the two vision conditions at 5% of maximal voluntary contraction. All dependent variables were analyzed in two-way mixed model (Group × Vision Condition; 2 × 2) ANOVAs with repeated measures on the last factor. RESULTS: The analyses revealed that older adults had greater mean force produced by two hands in both vision conditions (i.e., yes and no visual feedback). Across both vision conditions, the older adult group showed greater asymmetrical force variability (i.e., standard deviation of non-dominant hand > standard deviation of dominant hand) and revealed more positive correlation coefficients between forces produced by two hands as compared with the young adult group. Finally, an index of bilateral motor synergies was significantly greater in young adults than older adults when visual feedback was available. CONCLUSION: The current findings indicate that deficits in interlimb force coordination across multiple trials appeared in older adults.

Multimodal Intervention to Improve Functional Status in Hypertensive Older Adults: A Pilot Randomized Controlled Trial.

This pilot randomized controlled trial (RCT) was designed to provide the preliminary data necessary to conduct a full-scale trial to compare the efficacy of differing first-line antihypertensive medications in improving functional status in older adults, when combined with exercise. The primary objectives were to assess study feasibility, safety, and protocol integrity. Dependent outcomes included gait speed, exercise capacity, body composition, and systemic cardiometabolic biomarkers. Thirty-one physically inactive older adults (70.6 ± 6.1 years) with hypertension and functional limitations were randomly assigned to 1) Perindopril (8 mg/day n = 10), 2) Losartan (100 mg/day; n = 13), or 3) Hydrochlorothiazide (HCTZ: 25 mg/day; n = 8). Participants were also assigned to a 24-week multimodal exercise intervention, separated into an aerobic and concurrent (aerobic + resistance) phase to evaluate potential mode effects. Retention was 84% (26/31), and compliance was >90% and >79% with medication and exercise, respectively. A total of 29 adverse events (Perindopril = 5; Losartan = 12; HCTZ = 11) and one unrelated serious adverse event were observed throughout the trial. Overall, this pilot RCT provided critical data and identified several challenges to ultimately designing and implementing a fully powered trial.

Blood-Flow Restriction Resistance Exercise for Older Adults with Knee Osteoarthritis: A Pilot Randomized Clinical Trial.

In a pilot randomized clinical trial, participants aged ≥60 years (n = 35) with physical limitations and symptomatic knee osteoarthritis (OA) were randomized to 12 weeks of lower-body low-load resistance training with blood-flow restriction (BFR) or moderate-intensity resistance training (MIRT) to evaluate changes in muscle strength, pain, and physical function. Four exercises were performed three times per week to volitional fatigue using 20% and 60% of one repetition maximum (1RM). Study outcomes included knee extensor strength, gait speed, Short Physical Performance Battery (SPPB) performance, and pain via the Western Ontario and McMaster Universities OA Index (WOMAC). Per established guidance for pilot studies, primary analyses for the trial focused on safety, feasibility, and effect sizes/95% confidence intervals of dependent outcomes to inform a fully-powered trial. Across three speeds of movement, the pre- to post-training change in maximal isokinetic peak torque was 9.96 (5.76, 14.16) Nm while the mean difference between groups (BFR relative to MIRT) was -1.87 (-10.96, 7.23) Nm. Most other directionally favored MIRT, though more spontaneous reports of knee pain were observed (n = 14) compared to BFR (n = 3). BFR may have lower efficacy than MIRT in this context-though a fully-powered trial is needed to definitively address this hypothesis.

Angiotensin Converting Enzyme Inhibitors Combined with Exercise for Hypertensive Seniors (The ACES Trial): Study Protocol of a Randomized Controlled Trial.

Prior evidence suggests that the choice of antihypertensive medication may influence functional status among older adults with hypertension, particularly in conjunction with exercise. In particular, angiotensin converting enzyme (ACE) inhibitors have shown potential to positively influence function. However, randomized, controlled trials are needed to confirm this hypothesis. This paper outlines an RCT designed to determine if choice of first-line antihypertensive medication influences functional and cardiovascular risk factor responses to exercise among older adults with hypertension. Two hundred and thirteen inactive, community-dwelling adults ≥60 years of age with hypertension and functional limitations will be recruited to engage in a 32-week intervention study. Participants will be randomized to one of three first-line antihypertensive agents: (1) the ACE inhibitor perindopril, (2) the AT1 receptor antagonist losartan, or (3) the thiazide diuretic hydrochlorothiazide (HCTZ). Six weeks after randomization, participants will begin a 20-week structured aerobic exercise intervention. Participants will perform two 45-min center-based sessions coupled with 60 min of home-based walking per week. The primary aim is to determine if perindopril improves self-paced gait speed when compared with losartan and HCTZ. The secondary aim is to determine the relative effect of perindopril on secondary outcomes such as: (a) exercise capacity, (b) body mass and composition, and (c) circulating indices of cardiovascular risk. This RCT is expected to identify differential effects of first-line antihypertensive medications when combined with physical exercise thus have potential implications for antihypertensive prescription guidelines for older adults. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03295734.

Extraperitoneal endometriosis with catamenial pneumothoraces: a review of the literature.

OBJECTIVE: To present a case of recurrent catamenial pneumothorax and diaphragmatic endometriosis that was managed thoracoscopically. A review of the literature is also presented. METHODS: A-28-year-old woman presented with bloody stools, chronic constipation, and chest pain. A review of systems was positive for monthly chest pain associated with her menses. A preoperative chest x-ray revealed a right pneumothorax. Colonoscopy revealed biopsy proven endometriosis of the sigmoid colon. A pelvic computed tomography scan revealed bilateral complex, cystic and solid adenexal lesions. RESULTS: A right thoracoscopy was performed. A lesion on the right hemidiaphragm was excised and confirmed to be endometriosis. A wedge section of lung tissue containing a bleb was resected and also contained endometriosis. Three months later, the patient underwent laparoscopic excision of her pelvic endometriosis, including a low anterior rectal resection. Five months later, she presented again with right-sided chest pain. A thoracoscopic right total pleurectomy was performed for recurrent pneumothorax. CONCLUSION: Pullmonary endometriosis may present as chest pain, shortness of breath, or hemoptysis associated with menstrual cycles. This case emphasizes the importance of a careful review of systems in patients with known endometriosis. Management now includes an endoscopic alternative and all of its known benefits.

Effects of laparoscopic lavage on adhesion formation and peritoneum in an animal model of pelvic inflammatory disease.

STUDY OBJECTIVES: To develop an animal model of pelvic inflammatory disease (PID) that simulates intraluminal tubal damage and adhesion formation seen in human PID, and to evaluate peritoneal effects of laparoscopic lavage with 1% povidone-iodine, 0.5% povidone-iodine, and 0.05% chlorhexidine gluconate solutions. DESIGN: Prospective, randomized, controlled study (Canadian Task Force classification I). SETTING: Animal research operating room facility. SUBJECTS: Forty-five 1-year-old Pasteurella-free New Zealand white rabbits. INTERVENTION: Laparoscopy with instillation of one of five lavage solutions after bacterial inoculation with Neisseria gonorrhoeae, Bacteroides fragilis, Escherichia coli, and Peptococcus niger. MEASUREMENTS AND MAIN RESULTS: Histologic evaluation revealed significantly more peritoneal inflammation after lavage with all three solutions than after no lavage or lavage with normal saline. Gross adhesion formation was visible in only one rabbit after lavage with normal saline. One animal having lavage with 1% povidone-iodine died immediately after injection for sedation before laparoscopic lavage, and was not included in the final results. CONCLUSION: Bacterial inoculation using an intrauterine insemination catheter did not produce clinical adhesions in 43 of 44 rabbits. Histologic evaluation revealed significantly more peritoneal inflammation in the lavage with povidone-iodine and chlorhexidine gluconate compared with no lavage or lavage with normal saline.