Physiological determinants of mechanical efficiency during advanced ageing and disuse.

This study aimed to determine which physiological factors impact net efficiency (ηnet) in oldest-old individuals at different stages of skeletal muscle disuse. To this aim, we examined ηnet, central haemodynamics, peripheral circulation, and peripheral factors (skeletal muscle fibre type, capillarization and concentration of mitochondrial DNA [mtDNA]). Twelve young (YG; 25 ± 2 years), 12 oldest-old mobile (OM; 87 ± 3 years), and 12 oldest-old immobile (OI; 88 ± 4 years) subjects performed dynamic knee extensor (KE) and elbow flexors (EF) exercise. Pulmonary oxygen uptake, photoplethysmography, Doppler ultrasound and muscle biopsies of the vastus lateralis and biceps brachii were used to assess central and peripheral adaptations to advanced ageing and disuse. Compared to the YG (12.1 ± 2.4%), the ηnet of lower-limb muscle was higher in the OM (17.6 ± 3.5%, P < 0.001), and lower in the OI (8.9 ± 1.9%, P < 0.001). These changes in ηnet during KE were coupled with significant peripheral adaptations, revealing strong correlations between ηnet and the proportion of type I muscle fibres (r = 0.82), as well as [mtDNA] (r = 0.77). No differences in ηnet were evident in the upper-limb muscles between YG, OM and OI. In view of the differences in limb-specific activity across the lifespan, these findings suggest that ηnet is reduced by skeletal muscle inactivity and not by chronological age, per se. Likewise, this study revealed that the age-related changes in ηnet are not a consequence of central or peripheral haemodynamic adaptations, but are likely a product of peripheral changes related to skeletal muscle fibre type and mitochondrial density. KEY POINTS: Although the effects of ageing and muscle disuse deeply impact the cardiovascular and skeletal muscle function, the combination of these factors on the mechanical efficiency are still a matter of debate. By measuring both upper- and lower-limb muscle function, which experience differing levels of disuse, we examined the influence of central and peripheral haemodynamics, and skeletal muscle factors linked to mechanical efficiency. Across the ages and degree of disuse, upper-limb muscles exhibited a preserved work economy. In the legs the oldest-old without mobility limitations exhibited an augmented mechanical efficiency, which was reduced in those with an impairment in ambulation. These changes in mechanical efficiency were associated with the proportion of type I muscle fibres. Recognition that the mechanical efficiency is not simply age-dependent, but the consequence of inactivity and subsequent skeletal muscle changes, highlights the importance of maintaining physical activity across the lifespan.

Relationships are everything: The underpinnings of grassroots community action in the COVID-19 pandemic in Toronto.

Most government emergency/pandemic response plans feature top-down decision making and communication strategies and a focus on 'hard' (physical) infrastructure. There is nothing about the importance of the ideas and communications originating from communities, the social infrastructure that supports their impact locally and their contribution to the central administration. In this study, we found that the 'soft' (social) infrastructure within communities and between communities and formal institutions is key to an inclusive and more equitable response to large-scale crises like the COVID-19 pandemic. Grassroots leaders in six Toronto neighbourhoods were interviewed between the first and second waves of the COVID-19 pandemic in Toronto about what helped or hindered community action. Three themes emerged: (1) Grassroots leaders and community organizations were able to act as key connection points in a two-way flow of information and resources with residents and service providers; (2) Grassroots leaders and groups were challenged to engage in this work in a sustained capacity without adequate resourcing; and (3) there was a disconnect between community-centred grassroots approaches and the City's emergency response. We conclude that there needs to be pre-disaster investment in community level planning and preparation that fosters two-way connections between all municipal emergency/disaster and pandemic preparedness plans and community-centred organizations and grassroots leaders working in marginalized communities.

A Call to Action to Review the USPSTF's Recommendation for Testicular Self-Examination.

We urge the United States Preventive Services Task Force (USPSTF) to call for a formal review of the evidence regarding testicular self-examination (TSE). Twelve years have since passed since the evidence was last formally analyzed where normally re-reviews occur in 5-year cycles. If they would decide to move forward with this action, we ask for the USPSTF to review their methods for establishing recommendations to optimize their rating system operationalization process. Finally, emerging evidence demonstrates a net positive effect of TSE. This stands in contrast to the assertions of TSE's supposed harm that is prevalent in the literature as well as the rationale behind the USPSTF's "D" rating of TSE.

A Realist Approach to Analysis in a Participatory Research Project.

BACKGROUND: Realist reviews have shown the effectiveness of participatory action research but the realist approach has not been used in combination with a participatory approach in qualitative data analysis. OBJECTIVES: To study the links between preexisting conditions in neighborhoods and the kind of actions taken at the community level during the coronavirus disease 2019 pandemic in Toronto, a community-university research partnership used a critical realist approach to analyze qualitative interviews with grassroots leaders. This article describes the procedures developed to enable participation of the full community- academic team in the analysis. METHODS: One analyst coded paragraphs in all 46 interviews for preexisting conditions (contexts), actions taken (intervention components), the often implicit factors that underpinned the actions (mechanisms), and observed results (outcomes) as stated by the interviewees. Each interview was summarized in terms of the contexts (C), actions (I), mechanisms (M) and outcomes (O) identified and one to seven midrange CIMO hypotheses were developed for each interview. A second level of analysis involved sense-making workshops with the community partner and a cross-section of interviewees using the CIMO statements. CONCLUSIONS: This article describes the realist approach to analysis and the changes that were made to enable a mixed team of community leaders and academics to generate overall statements of impact. This is a novel approach to qualitative data analysis, with a range of implications for the use of this technique in participatory research.

A connected community response to COVID-19 in Toronto.

In this commentary, we describe initial learnings from a community-based research project that explored how the relational space between residents and formal institutions in six marginalised communities in Toronto, Ontario, Canada impacted grassroots responses to the health and psycho-social stresses that were created and amplified by the coronavirus disease 2019 (COVID-19) pandemic. Our research found that grassroots community leaders stepped up to fill the gaps left by Toronto's formal public health and emergency management systems and were essential for mitigating the psycho-social and socioeconomic impacts of the pandemic that exacerbated pre-existing inequities and systemic failures. We suggest that building community resilience in marginalised communities in Toronto can embody health promotion in action where community members, organisational, institutional and government players create the social infrastructure necessary to build on local assets and work together to promote health by strengthening community action, advocating for healthy public policy and creating supportive environments.

A Connected Community Approach: Citizens and Formal Institutions Working Together to Build Community-Centred Resilience.

Urban resilience research is recognizing the need to complement a mainstream preoccupation with "hard" infrastructure (electrical grid, storm sewers, etc.) with attention to the "soft" (social) infrastructure issues that include the increased visibility of and role for civil society, moving from (top-down, paternalistic) government to (participatory) governance. Analyses of past shock events invariably point to the need for more concerted efforts in building effective governance and networked relations between civil society groupings and formal institutions before, during, and after crisis. However, the literature contains little advice on how to go about this. In this paper, we advance a Connected Community Approach (CCA) to building community resilience with a specific focus on the relationship between community and formal institutions. In the literature review that informs this work, we assess the current, limited models for connecting communities to formal institutions, as well as the emerging role of community-based organizations in this work, and we offer our own assessment of some of the key tensions, lacunae, and trends in the community resilience field. Principally, we explore the potential of the CCA model, as spearheaded by the East Scarborough Storefront and the Centre for Connected Communities in Toronto, Canada, as a promising approach for building the relational space between civil society and the state that is so often called for in the literature. The paper concludes with future directions for research and practice.

Mitochondrial Oxidative Phosphorylation defect in the Heart of Subjects with Coronary Artery Disease.

Coronary artery disease (CAD) is a leading cause of death worldwide and frequently associated with mitochondrial dysfunction. Detailed understanding of abnormalities in mitochondrial function that occur in patients with CAD is lacking. We evaluated mitochondrial damage, energy production, and mitochondrial complex activity in human non-CAD and CAD hearts. Fresh and frozen human heart tissue was used. Cell lysate or mitochondria were isolated using standard techniques. Mitochondrial DNA (mtDNA), NAD + and ATP levels, and mitochondrial oxidative phosphorylation capacity were evaluated. Proteins critical to the regulation of mitochondrial metabolism and function were also evaluated in tissue lysates. PCR analysis revealed an increase in mtDNA lesions and the frequency of mitochondrial common deletion, both established markers for impaired mitochondrial integrity in CAD compared to non-CAD patient samples. NAD+ and ATP levels were significantly decreased in CAD subjects compared to Non-CAD (NAD+ fold change: non-CAD 1.00 ± 0.17 vs. CAD 0.32 ± 0.12* and ATP fold change: non-CAD 1.00 ± 0.294 vs. CAD 0.01 ± 0.001*; N = 15, P < 0.005). We observed decreased respiration control index in CAD tissue and decreased activity of complexes I, II, and III. Expression of ETC complex subunits and respirasome formation were increased; however, elevations in the de-active form of complex I were observed in CAD. We observed a corresponding increase in glycolytic flux, indicated by a rise in pyruvate kinase and lactate dehydrogenase activity, indicating a compensatory increase in glycolysis for cellular energetics. Together, these results indicate a shift in mitochondrial metabolism from oxidative phosphorylation to glycolysis in human hearts subjects with CAD.

Endogenous endothelin-1 and femoral artery shear rate: impact of age and implications for atherosclerosis.

BACKGROUND: Both altered shear rate and endothelin-1 (ET-1) are associated with the age-related development of atherosclerosis. However, the role of ET-1, a potent endogenous vasoconstrictor, in altering shear rate in humans, especially in the atherosclerotic-prone vasculature of the leg, is unknown. Therefore, this study examined the contribution of ET-1 to the age-related alterations in common femoral artery (CFA) shear rate. METHOD: BQ-123, a specific endothelin type A (ET(A)) receptor antagonist, was infused into the CFA, and diameter and blood velocity were measured by Doppler ultrasound in young (n = 8, 24 ±â€Š2 years) and old (n = 9, 70 ±â€Š2 years) study participants. RESULTS AND CONCLUSION: The old had greater intima-media thickening in the CFA, indicative of a preatherogenic phenotype. Prior to infusion, the old study participants exhibited reduced mean shear rate (27 ±â€Š3/s) compared with the young study participants (62 ±â€Š9/s). This difference was likely driven by attenuated antegrade shear rate in the old as retrograde shear rate was similar in the young and old. Inhibition of ETA receptors, by BQ-123, increased leg blood flow in the old, but not in the young, abolishing age-related differences. Older study participants had a larger CFA (young: 0.82 ±â€Š0.03 cm, old: 0.99 ±â€Š0.03 cm) in which BQ-123 induced significant vasodilation (5.1 ±â€Š1.0%), but had no such effect in the young (-0.8 ±â€Š0.8%). Interestingly, despite the age-specific, BQ-123-induced increase in leg blood flow and CFA diameter, shear rate patterns remained largely unchanged. Therefore, ET-1, acting through the ETA receptors, exerts a powerful age-specific vasoconstriction. However, removal of this vasoconstrictor stimulus does not augment mean shear rate in the old.

Endothelin-A-mediated vasoconstriction during exercise with advancing age.

The endothelin-1 vasoconstrictor pathway contributes to age-related elevations in resting peripheral vascular tone primarily through activation of the endothelin subtype A (ET(A)) receptor. However, the regulatory influence of ET(A)-mediated vasoconstriction during exercise in the elderly is unknown. Thus, in 17 healthy volunteers (n = 8 young, 24±2 years; n = 9 old, 70±2 years), we examined leg blood flow, mean arterial pressure, leg arterial-venous oxygen (O2) difference, and leg O2 consumption (VO2) at rest and during knee-extensor exercise before and after intra-arterial administration of the ET(A) antagonist BQ-123. During exercise, BQ-123 administration increased leg blood flow to a greater degree in the old (+29±5 mL/min/W) compared with the young (+16±3 mL/min/W). The increase in leg blood flow with BQ-123 was accompanied by an increase in leg VO2 in both groups, suggesting a reduced efficiency following ET(A) receptor blockade. Together, these findings have identified an age-related increase in ET(A)-mediated vasoconstrictor activity that persists during exercise, suggesting an important role of this pathway in the regulation of exercising skeletal muscle blood flow and maintenance of arterial blood pressure in the elderly.

Cellular aging of skeletal muscle: telomeric and free radical evidence that physical inactivity is responsible and not age.

Telomeres play an essential role in maintaining chromosomal integrity in the face of physiological stressors. Although the age-related shortening of TL (telomere length) in highly proliferative tissue is predominantly due to the replication process, the mechanism for telomere shortening in skeletal muscle, which is minimally proliferative, is unclear. By studying TL in both the upper and lower limbs of the young, old-mobile and old-immobile subjects and by virtue of the bipedal nature of human locomotion, which declines with age, it may be possible to elucidate the mechanism(s) responsible for cellular aging of skeletal muscle. With this approach, we revealed that TL (~15 kb) in arm skeletal muscle is unaffected by age. In contrast TL fell progressively in the legs across the young (~15 kb), the old mobile (~13 kb) and old immobile (~11 kb) subjects. Interestingly, there was a reciprocal increase in leg muscle free radicals across these groups that was correlated with TL (r=0.7), with no such relationship in the arm (r=0.09). Our results document that chronological age does not affect the cellular aging of skeletal muscle, but reveals that physical inactivity, probably mediated by free radicals, has a profound effect upon this process.

Taming the "sleeping giant": the role of endothelin-1 in the regulation of skeletal muscle blood flow and arterial blood pressure during exercise.

The cardiovascular response to exercise is governed by a combination of vasodilating and vasoconstricting influences that optimize exercising muscle perfusion while protecting mean arterial pressure (MAP). The degree to which endogenous endothelin (ET)-1, the body's most potent vasoconstrictor, participates in this response is unknown. Thus, in eight young (24 ± 2 yr), healthy volunteers, we examined leg blood flow, MAP, tissue oxygenation, heart rate, leg arterial-venous O(2) difference, leg O(2) consumption, pH, and net ET-1 and lactate release at rest and during knee extensor exercise (0, 5, 10, 15, 20, and 30 W) before and after an intra-arterial infusion of BQ-123 [ET subtype A (ET(A)) receptor antagonist]. At rest, BQ-123 did not evoke a change in leg blood flow or MAP. During exercise, net ET-1 release across the exercising leg increased approximately threefold. BQ-123 increased leg blood flow by ~20% across all work rates (changes of 113 ± 76, 176 ± 83, 304 ± 108, 364 ± 130, 502 ± 117, and 570 ± 178 ml/min at 0, 5, 10, 15, 20, and 30 W, respectively) and attenuated the exercise-induced increase in MAP by ~6%. The increase in leg blood flow was accompanied by a ~9% increase in leg O(2) consumption with an unchanged arterial-venous O(2) difference and deoxyhemoglobin, suggesting a decline in intramuscular efficiency after ET(A) receptor blockade. Together, these findings identify a significant role of the ET-1 pathway in the cardiovascular response to exercise, implicating vasoconstriction via the ET(A) receptor as an important mechanism for both the restraint of blood flow in the exercising limb and maintenance of MAP in healthy, young adults.