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The accumulation of dysfunctional mitochondria has been implicated in aging, but a deeper understanding of mitochondrial dynamics and mitophagy during aging is missing. Here, we show that upregulating Drp1—a Dynamin-related protein that promotes mitochondrial fission—in midlife, prolongs Drosophila lifespan and healthspan. We find that short-term induction of Drp1, in midlife, is sufficient to improve organismal health and prolong lifespan, and observe a midlife shift toward a more elongated mitochondrial morphology, which is linked to the accumulation of dysfunctional mitochondria in aged flight muscle. Promoting Drp1-mediated mitochondrial fission, in midlife, facilitates mitophagy and improves both mitochondrial respiratory function and proteostasis in aged flies. Finally, we show that autophagy is required for the anti-aging effects of midlife Drp1-mediated mitochondrial fission. Our findings indicate that interventions that promote mitochondrial fission could delay the onset of pathology and mortality in mammals when applied in midlife. Mitochondrial fission and fusion are important mechanisms to maintain mitochondrial function. Here, the authors report that middle-aged flies have more elongated, or ‘hyper-fused’ mitochondria, and show that induction of mitochondrial fission in midlife, but not in early life, extends the health and life of flies.

Background Low muscle oxidative capacity is an extrapulmonary manifestation of chronic obstructive pulmonary disease (COPD) with unclear aetiology. We sought to characterize locomotor muscle oxidative capacity in never smokers and ever smokers with and without COPD and determine clinical and behavioural features associated with low muscle oxidative capacity. Methods Two hundred forty‐three adults enrolled in the Muscle Health Study, an observational study ancillary to COPDGene. Gastrocnemius oxidative capacity was measured by near‐infrared spectroscopy from the muscle oxygen consumption recovery rate constant (k). Physical activity was measured by accelerometry (vector magnitude units [VMU]/min). Pulmonary assessments included spirometry (FEV1%predicted), diffusing capacity (DLCO) and quantitative chest computed tomography (CT). Eighty‐seven variables related to COPD features were considered. Variables selected by univariate analysis of log‐transformed k with p ≤ 0.20 and filtered by machine learning were entered into multivariable linear regression to determine association with k. Results Two hundred forty‐one (53.1% female; 45.6% African American; 64 ± 10 years old) participants were allocated to analysis. FEV1%predicted, DLCO, CT, pack‐years, age and VMU/min were among 24 variables selected by univariate analysis. After machine learning filtering on 162 (67%) cases with complete data, 11 variables were included in multivariable analysis. Only FEV1%predicted, age and race were significantly associated with k (R2 = 0.26). Model coefficients equate a 10% lower FEV1%predicted to a 4.4% lower k or 10 years of aging to a 9.7% lower k. In 118 cases with CT available, FEV1%predicted and age remained associated with k (R2 = 0.24). Physical activity was not retained in any model. Conclusions Physical activity or radiographic COPD manifestations were not significantly associated with muscle oxidative impairment. Across never smokers and ever smokers with and without COPD, locomotor muscle oxidative capacity was positively associated with FEV1%predicted and negatively associated with age.

Expiratory flow limitation results in dynamic hyperinflation, dyspnoea and premature exercise intolerance. We aimed to measure whether expiratory resistance reduces locomotor power via limiting maximal voluntary motor activity, exacerbating muscle fatigue, or both. Healthy volunteers ( n  = 14; 23 (3) years) performed a series of very heavy‐domain constant power cycling exercise tests with and without an imposed expiratory flow resistance (7 cmH 2 O/L/s). The decline in maximal evocable isokinetic power at intolerance during each experimental condition was apportioned to: (1) the power equivalent from a reduction in maximum voluntary muscle activation (termed ‘activation fatigue’); and (2) the deficit in expected power at a given isokinetic muscle activity (muscle fatigue). Imposed expiratory resistance reduced exercise tolerance (487 (145) vs. 575 (137) s; 95% confidence interval of the difference (CI diff ) 52, 125 s; P = 0.0002). At isotime‐control, imposed expiratory resistance resulted in a greater decline in inspiratory reserve volume (CI diff 0.20, 0.94 L; P = 0.007), and increased dyspnoea (Borg CR‐10; CI diff 0.7, 3.0; P = 0.006) than without. Muscle fatigue was unaffected (CI diff −20, 17 W; P = 0.873), but activation fatigue was greater with expiratory resistance (CI diff 1, 49 W; P = 0.044) and related to the reduction in inspiratory reserve volume ( r 2  = 0.53; P = 0.028). As a result, locomotor power reserve was reduced with expiratory resistance (253 (83) vs. 201 (92) W; CI diff −10, 113; P = 0.09). Imposed expiratory resistive loading initiated a cascade of abnormal lung mechanics and symptoms. These abnormalities conflate to reduce exercise tolerance through limiting maximal voluntary motor activity. What is the central question of this study? Resistance to expiration, such as in asthma and chronic obstructive lung disease, causes abnormal lung function and intolerance to exercise: does abnormal lung mechanics directly affect locomotor fatigue? What is the main finding and its importance? Imposed expiratory resistance initiates a cascade of abnormal lung mechanics and symptoms, which conflate to reduce exercise tolerance through limiting maximal voluntary motor activity.

Tidal breathing in awake humans is variable. This variability causes changes in lung gas stores that affect gas exchange measurements. To overcome this, several algorithms provide solutions for breath‐by‐breath alveolar gas exchange measurement; however, there is no consensus on a physiologically robust method suitable for widespread application. A recent approach, the ‘independent‐breath’ (IND) algorithm, avoids the complexity of measuring breath‐by‐breath changes in lung volume by redefining what is meant by a ‘breath’. Specifically, it defines a single breathing cycle as the time between equal values of the FO2 ${F_{{{\\mathrm{O}}_2}}}$ /FN2 ${F_{{{\\mathrm{N}}_2}}}$(or FCO2 ${F_{{\\mathrm{C}}{{\\mathrm{O}}_2}}}$ /FN2 ${F_{{{\\mathrm{N}}_2}}}$ ) ratio, that is, the ratio of fractional concentrations of lung‐expired O2 (or CO2) and nitrogen (N2). These developments imply that the end of one breath is not, by necessity, aligned with the start of the next. Here we demonstrate how the use of the IND algorithm fails to conserve breath‐by‐breath mass balance of O2 and CO2 exchanged between the atmosphere and tissues (and vice versa). We propose a new term, within the IND algorithm, designed to overcome this limitation. We also present the far‐reaching implications of using algorithms based on alternative definitions of the breathing cycle, including challenges in measuring and interpreting the respiratory exchange ratio, pulmonary gas exchange efficiency, dead space fraction of the breath, control of breathing, and a broad spectrum of clinically relevant cardiopulmonary exercise testing variables. Therefore, we do not support the widespread adoption of currently available alternative definitions of the breathing cycle as a legitimate solution for breath‐by‐breath alveolar gas exchange measurement in research or clinical settings. What is the central question of this study? The IND algorithm for breath‐by‐breath alveolar gas exchange computation redefines ‘a breath’: what are the implications of this approach for the measurement of gas exchange at rest and during exercise? What is the main finding and its importance? The IND algorithm does not maintain continuity between consecutive breaths, violating the conservation of mass for breath‐by‐breath alveolar gas exchange measurements. A volume correction to the algorithm is provided to address this discrepancy and preserve mass balance. However, by redefining the conventional breathing cycle, the IND algorithm has additional implications for cardiopulmonary exercise testing interpretation because variables with demonstrated diagnostic and prognostic value cannot be accurately determined.

This study aimed to evaluate in vivo oxidative capacity and relative resistance to O2 diffusion using near‐infrared spectroscopy (NIRS) in the m. triceps brachii of recreational to world class swimmers and evaluate their relationships with swimming performance. Twenty‐eight swimmers were enrolled and assigned into three subgroups according to their level: ‘recreational/trained’ (Tier 1/2; n = 8), ‘national’ (Tier 3; n = 12) and ‘international/world class’ (Tier 4/5; n = 8). Performance was evaluated by 100 m freestyle trials. Training volume was measured by self‐reported distance (km/week). The mV̇O2 ${\\mathrm{m}}{{\\dot{V}}_{{{\\mathrm{O}}}_{\\mathrm{2}}}$recovery k of m. triceps brachii was non‐invasively estimated by NIRS through repeated intermittent occlusions under two conditions: well‐oxygenated (kHIGH) and low O2 availability (kLOW). The difference between kHIGH and kLOW (Δk) was calculated as an index of relative resistance to O2 diffusion. FINA points and 100 m performance differed among all groups. Training volume was greater in Tier 4/5 (34.0 ± 5.5 km week−1) and Tier 3 (35.5 ± 11.6 km week−1) than in Tier 1/2 (6.4 ± 1.8 km week−1). kHIGH was greater in Tier 4/5 and Tier 3 (3.18 ± 0.41 and 2.79 ± 0.40 min−1) versus Tier 1/2 (2.10 ± 0.36 min−1; all P < 0.002). kHIGH correlated with FINA points, 100 m performance and training volume. ∆k was not different among tiers and was not associated with training volume or performance. M. triceps brachii oxidative capacity (kHIGH) was positively associated with performance and training volume in swimmers. ∆k, which reflects relative resistance to O2 diffusion, was not different among athletes. These data suggest that m. triceps brachii oxidative capacity is associated with swimming performance and that muscle O2 diffusing capacity exerts a similar relative resistance to O2 diffusive flow across swimmers. What is the central question of this study? Do highly trained swimmers have greater muscle oxidative capacity but higher sensitivity to reductions in O2 availability, that is, are relatively more ‘O2 diffusion limited’, than recreational swimmers? What is the main finding and its importance? We found that m. triceps brachii oxidative capacity varied significantly among swimmers of different competitive levels, and that it was associated with both training volume and performance. However, relative resistance to O2 diffusion was not different among swimmers of all levels, suggesting that training‐induced adaptations to support muscle oxidative capacity were matched well to adaptations to support muscle O2 diffusion.

Increasingly end-organ injury is being demonstrated late after institution of the Fontan circulation, particularly liver fibrosis and cirrhosis. The exact mechanisms for these late phenomena remain largely elusive. Hypothesizing that exercise induces precipitous systemic venous hypertension and insufficient cardiac output for the exercise demand, that is, a possible mechanism for end-organ injury, we sought to demonstrate the dynamic exercise responses in systemic venous perfusion (SVP) and concurrent end-organ perfusion. Ten stable Fontan patients and 9 control subjects underwent incremental cycle ergometry–based cardiopulmonary exercise testing. SVP was monitored in the right upper limb, and regional tissue oxygen saturation was monitored in the brain and kidney using near-infrared spectroscopy. SVP rose profoundly in concert with workload in the Fontan group, described by the regression equation 15.97 + 0.073 watts per mm Hg. In contrast, SVP did not change in healthy controls. Regional renal (p <0.01) and cerebral tissue saturations (p <0.001) were significantly lower and decrease more rapidly in Fontan patients. We conclude that in a stable group of adult patients with Fontan circulation, high-intensity exercise was associated with systemic venous hypertension and reduced systemic oxygen delivery. This physiological substrate has the potential to contribute to end-organ injury.