Editorial Commentary: SCR: Substantial Confusion Remains.

Superior capsular reconstruction is gaining acceptance as a procedure to treat massive and irreparable superior and posterosuperior rotator cuff tears. With a paucity of clinical and no long-term data, early results suggest that superior capsular reconstruction may offer improvements in pain, range of motion, function, and validated outcome measurements.

The influence of maturation on the oxygen uptake efficiency slope.

This study examined the influence of maturation on the oxygen uptake efficiency slope (OUES) in healthy male subjects. Seventy-six healthy male subjects (8-27 yr) were divided into groups based on maturation status: prepubertal (PP), midpubertal (MP), late-pubertal (LP), and young-adult (YA) males. Puberty status was determined by physical examination. Subjects performed a graded exercise test on a cycle ergometer to determine OUES. Group differences were assessed using a one-way ANOVA. OUES values (VO(2)L·min(-1)/log(10)V(E)L·min(-1)) were lower in PP and MP compared with LP and YA (p < .05). When OUES was expressed relative to body mass (VO(2)mL·kg-1·min(-1)/log(10)V(E)mL·kg(-1)·min(-1)) differences between groups reversed whereby PP and MP had higher mass relative OUES values compared with LP and YA (p < .05). Adjusting OUES by measures of body mass failed to eliminate differences across maturational groups. This suggests that qualitative factors, perhaps related to oxidative metabolism, account for the responses observed in this study.

Role of Collagen in Airway Mechanics.

Collagen is the most abundant airway extracellular matrix component and is the primary determinant of mechanical airway properties. Abnormal airway collagen deposition is associated with the pathogenesis and progression of airway disease. Thus, understanding how collagen affects healthy airway tissue mechanics is essential. The impact of abnormal collagen deposition and tissue stiffness has been an area of interest in pulmonary diseases such as cystic fibrosis, asthma, and chronic obstructive pulmonary disease. In this review, we discuss (1) the role of collagen in airway mechanics, (2) macro- and micro-scale approaches to quantify airway mechanics, and (3) pathologic changes associated with collagen deposition in airway diseases. These studies provide important insights into the role of collagen in airway mechanics. We summarize their achievements and seek to provide biomechanical clues for targeted therapies and regenerative medicine to treat airway pathology and address airway defects.

Regeneration of partially decellularized tracheal scaffolds in a mouse model of orthotopic tracheal replacement.

Decellularized tracheal scaffolds offer a potential solution for the repair of long-segment tracheal defects. However, complete decellularization of trachea is complicated by tracheal collapse. We created a partially decellularized tracheal scaffold (DTS) and characterized regeneration in a mouse model of tracheal transplantation. All cell populations except chondrocytes were eliminated from DTS. DTS maintained graft integrity as well as its predominant extracellular matrix (ECM) proteins. We then assessed the performance of DTS in vivo. Grafts formed a functional epithelium by study endpoint (28 days). While initial chondrocyte viability was low, this was found to improve in vivo. We then used atomic force microscopy to quantify micromechanical properties of DTS, demonstrating that orthotopic implantation and graft regeneration lead to the restoration of native tracheal rigidity. We conclude that DTS preserves the cartilage ECM, supports neo-epithelialization, endothelialization and chondrocyte viability, and can serve as a potential solution for long-segment tracheal defects.

The long-term residual effects of low-magnitude mechanical stimulation therapy on skeletal health.

BACKGROUND: Low-magnitude mechanical stimulation (LMMS) may improve skeletal health. The objective of this research was to investigate the long-term residual effects of LMMS on bone health. 10-week old female mice were given LMMS for 8 weeks; SHAM did not receive LMMS. Some groups remained on study for an additional 8 or 16 weeks post treatment (N = 17). RESULTS: Epiphyseal trabecular mineralizing surface to bone surface ratio (MS/BS) and bone formation rate (BFR/BS) were significantly greater in the LMMS group compared to the SHAM group at 8 weeks by 92 and 128% respectively. Mineral apposition rate (MAR) was significantly greater in the LMMS group 16 weeks post treatment by 14%.Metaphyseal trabecular bone mineral density (BMD) increased by 18%, bone volume tissue volume ratio (BV/TV) increased by 37%, and trabecular thickness (Tb.Th.) increased by 10% with LMMS at 8 weeks post treatment. Significant effects 16 weeks post treatment were maintained for BV/TV and Tb.Th. The middle-cortical region bone volume (BV) increased by 4% and cortical thickness increased by 3% with 8-week LMMS. CONCLUSIONS: LMMS improves bone morphological parameters immediately after and in some cases long-term post LMMS. Results from this work will be helpful in developing treatment strategies to increase bone health in younger individuals.

Immunopathogenesis and biomarkers of recurrent atrial fibrillation following ablation therapy in patients with preexisting atrial fibrillation.

INTRODUCTION: Recurrent atrial fibrillation (RAF) following ablation therapy occurs in about 50% of patients. The pathogenesis of RAF is unknown, but is believed to be driven by atrial remodeling in the setting of background inflammation. Structural, electrophysiological and mechanical remodeling has been associated with atrial fibrillation (AF). Inflammation and fibrotic remodeling are the major factors perpetuating AF, as mediators released from the atrial tissues and cardiomyocytes due to mechanical and surgical injury could initiate the inflammatory process. In this article, we have critically reviewed the key mediators that may serve as potential biomarkers to predict RAF. Areas covered: Damage associated molecular patterns, heat shock proteins, inflammatory cytokines, non-inflammatory markers, markers of inflammatory cell activity, and markers of collagen deposition and metabolism are evaluated as potential biomarkers with molecular treatment options in RAF. Expert commentary: Establishing biomarkers to predict RAF could be useful in reducing morbidity and mortality. Investigations into the role of DAMPs participating in a sterile immune response may provide greater insight into the pathogenesis of RAF. Markers evaluating immune cell activity, collagen deposition, and levels of heat shock proteins show the greatest promise as potential biomarkers to predict RAF and develop novel therapies.

Exercise responses in boys with attention deficit/hyperactivity disorder: effects of stimulant medication.

OBJECTIVE: The effect of stimulant medication on exercise responses was studied in 14 boys (10.9 +/- 1.1 years) with attention deficit/hyperactivity disorder (ADHD). METHOD: Exercise, with and without medication, was performed at 25 W, 50 W, and 75 W, followed by a peak exercise test. RESULT: Submaximal heart rate (HR) was significantly higher by ~8 to 13 b.min(-1) across the three intensities during the medication trial, but oxygen uptake (VO(2)), respiratory exchange ratio (RER), and perceived exertion were similar (p > .05). At peak exercise, VO(2), HR, and work rate were attenuated (p < or = .05) in the absence of medication but not RER or perceived exertion. The decreased peak exercise responses were apparent in 6 of 13 participants. CONCLUSION: Stimulant medication raises submaximal HR but does not affect other cardiorespiratory measures or perceived exertion. Without medication physiological responses at peak exercise are attenuated in some but not all boys with ADHD.

Appetite regulation in response to sitting and energy imbalance.

The impact of sitting and energy imbalance on appetite and appetite-regulating hormones (acylated ghrelin and leptin) was assessed in response to 1 day of sitting, with and without changes in energy intake. Fourteen men and women completed each of three 24-h conditions: high energy expenditure (standing) with energy balance (STAND), low energy expenditure (sitting) with energy surplus (SIT), and sitting with energy balance (SIT-BAL). Ghrelin, leptin, and appetite were measured in the fasted state and following a standardized meal. In the fasted state, there were no differences among conditions. Following the meal, ghrelin was lower in SIT than in STAND, with no change in appetite. When intake was reduced (SIT-BAL), the decrease in ghrelin when sitting was attenuated, hunger increased, and fullness decreased. SIT led to lower ghrelin concentrations in the men, whereas in the women, leptin increased. SIT-BAL led to an increase in ghrelin in the men but attenuated the leptin response, reduced ghrelin, increased hunger, and decreased fullness in the women. Because a dramatic reduction in energy expenditure was not accompanied by reduced appetite, prolonged sitting may promote excess energy intake, leading to weight gain in both men and women.

Effects of 1 day of inactivity on insulin action in healthy men and women: interaction with energy intake.

Prolonged periods of limited muscle activity can reduce insulin action. Acute changes in low muscle activity (ie, sitting) have not been assessed. In addition, unless energy intake is reduced during sitting to match low expenditure, the concurrent energy surplus may explain lower insulin action. The objective of the study was to evaluate the acute effect of sitting, with and without energy surplus, on insulin action. Fourteen young (26.1 ± 4.5 years, mean ± SD), nonobese (23.7% ± 7.1% fat), fit (peak oxygen consumption = 49.1 ± 3.3 mL·kg(-1)·min(-1)) men (n = 7) and women (n = 7) completed three 24-hour conditions: (1) an active, no-sitting condition (high energy expenditure of 2944 ± 124 kcal with energy intake matched to expenditure) = NO-SIT; (2) low energy expenditure (sitting) of 2195 ± 121 kcal with no reduction in energy intake (energy surplus) = SIT; and (3) sitting with energy intake reduced to 2139 ± 118 kcal to match low expenditure (energy balance) = SIT-BAL. Insulin action was measured the following morning during a continuous infusion of [6,6-(2)H]-glucose. Data were analyzed using linear mixed-effects models with planned contrasts. Compared with NO-SIT, insulin action, defined as whole-body rate of glucose disappearance normalized to mean plasma insulin, was reduced by 39% in SIT (P < .001) and by 18% in SIT-BAL (P = .07). Insulin action was higher in SIT-BAL compared with SIT (P = .04). One day of sitting considerably reduced insulin action; this effect was minimized, but not prevented, when energy intake was reduced to match expenditure. Strategies to limit daily sitting may reduce metabolic disease risk.

Metformin's effect on exercise and postexercise substrate oxidation.

Exercise and metformin may prevent or delay Type 2 diabetes by, in part, raising the capacity for fat oxidation. Whether the addition of metformin has additive effects on fat oxidation during and after exercise is unknown. Therefore, the purpose of this study was to evaluate the effect of metformin on substrate oxidation during and after exercise. Using a double-blind, counter-balanced crossover design, substrate oxidation was assessed by indirect calorimetry in 15 individuals taking metformin (2,000 mg/d) and placebo for 8-10 d. Measurements were made during cycle exercise at 5 submaximal cycle workloads, starting at 30% peak work (W(peak)) and increasing by 10% every 8 min to 70% W(peak). Substrate oxidation was also measured for 50 min postexercise. Differences between conditions were assessed using analysis of variance with repeated measures, and values are reported as M + or - SE. During exercise, fat oxidation (0.19 + or - 0.03 vs. 0.15 + or - 0.01 g/min, p < .01) and percentage of energy from fat (32% + or - 3% vs. 28% + or - 3%, p < .01) were higher with metformin than with placebo. Postexercise, metformin slightly lowered fat oxidation (0.12 + or - 0.02 to 0.10 + or - 0.02 g/min, p < .01) compared with placebo. There was an inverse relationship between postexercise fat oxidation and the rate of fat oxidation during exercise (r = -.68, p < .05). In healthy individuals, metformin has opposing actions on fat oxidation during and after exercise. Whether the same effects are evident in insulin-resistant individuals remains to be determined.

Effects of exercise on energy-regulating hormones and appetite in men and women.

When previously sedentary men and women follow exercise training programs with ad libitum feeding, men lose body fat, but women do not. The purpose of this study was to evaluate whether this observation could be related to sex differences in the way energy-regulating hormones and appetite perception respond to exercise. Eighteen (9 men, 9 women) overweight/obese individuals completed four bouts of exercise with energy added to the baseline diet to maintain energy balance (BAL), and four bouts without energy added to induce energy deficit (DEF). Concentrations of acylated ghrelin, insulin, and leptin, as well as appetite ratings were measured in response to a meal after a no-exercise baseline and both exercise conditions. In men, acylated ghrelin area under the curve (AUC) was not different between conditions. In women, acylated ghrelin AUC was higher after DEF (+32%) and BAL (+25%), and the change from baseline was higher than men (P < 0.05). In men, insulin AUC was reduced (-17%) after DEF (P < 0.05), but not BAL. In women, insulin AUC was lower (P < 0.05) after DEF (-28%) and BAL (-15%). Leptin concentrations were not different across conditions in either sex. In men, but not in women, appetite was inhibited after BAL relative to DEF. The results indicate that, in women, exercise altered energy-regulating hormones in a direction expected to stimulate energy intake, regardless of energy status. In men, the response to exercise was abolished when energy balance was maintained. The data are consistent with the paradigm that mechanisms to maintain body fat are more effective in women.

Impact of nutrient intake timing on the metabolic response to exercise.

Effects of nutrient intake timing and exercise on carbohydrate (e.g. insulin sensitivity), protein (muscle protein synthesis), and fat (circulating triacylglycerols) metabolism are reviewed in this paper. Altered nutrient intake timing relative to exercise can modulate the metabolic response, which is relevant for individuals seeking to use exercise to enhance health.

Impact of metformin on peak aerobic capacity.

Individually, exercise and the drug metformin have been shown to prevent or delay type 2 diabetes. Metformin mildly inhibits complex I of the electron transport system and may impact aerobic capacity in people exercising while taking metformin. The purpose of the study was to evaluate the effects of metformin on maximal aerobic capacity in healthy individuals without mitochondrial dysfunction. Seventeen healthy, normal-weight men (n=11) and women (n=6) participated in a double-blind, placebo-controlled, cross-over design. Peak aerobic capacity was measured twice using a continuous, incrementally graded protocol; once after 7-9 d of metformin (final dose=2000 mg/d) and once with placebo, with 1 week between tests. The order of the conditions was counterbalanced. Peak oxygen uptake (VO2 peak), heart rate (HR), ventilation (VE), respiratory exchange ratio (RER), rating of perceived exertion (RPE), and test duration were compared across conditions using paired t tests with the R statistical program. VO2 peak (-2.7%), peak heart rate (-2.0%), peak ventilation (-6.2%), peak RER (-3.0%), and exercise duration (-4.1%) were all reduced slightly, but significantly, with metformin (all p<0.05). There was no effect of metformin on RPE or ventilatory breakpoint. Correlations between the decrement in VO2 peak and any of the other outcome variables were weak (r2<0.20) and not significant. Short-term treatment with metformin has statistically significant, but physiologically subtle, effects that reduce key outcomes related to maximal exercise capacity. Whether this small but consistent effect is manifested in people with insulin resistance or diabetes who already have some degree of mitochondrial dysfunction remains to be determined.

The effect of carbohydrate availability following exercise on whole-body insulin action.

One bout of exercise enhances insulin-stimulated glucose uptake (insulin action), but the effect is blunted by consumption of carbohydrate-containing food after exercise. The independent roles of energy and carbohydrate in mediating post-exercise insulin action have not been systematically evaluated in humans. The purpose of this study was to determine if varying carbohydrate availability, with energy intake held constant, mediates post-exercise insulin action. Ten young (21 +/- 2 y, overweight (body fat 37% +/- 3%) men and women completed 3 conditions in random order: (i) no-exercise (BASE), (ii) exercise with energy balance but carbohydrate deficit (C-DEF), and (iii) exercise with energy and carbohydrate balance (C-BAL). In the exercise conditions, subjects expended 30% of total daily energy expenditure on a cycle ergometer at 70% VO2 peak. Following exercise, subjects consumed a meal that replaced expended energy (~3000 kJ) and was either balanced (intake = expenditure) or deficient (-100 g) in carbohydrate. Twelve hours later, insulin action was measured by continuous infusion of glucose with stable isotope tracer (CIG-SIT). Changes in insulin action were evaluated using a one-way ANOVA with repeated measures. During CIG-SIT, non-oxidative glucose disposal (i.e., glucose storage) was higher in C-DEF than in BASE (27.2 +/- 3.2 vs. 16.9 +/- 3.5 micromol.L-1.kg-1.min-1, p < 0.05). Conversely, glucose oxidation was lower in C-DEF (8.6 +/- 1.3 micromol.L-1.kg-1.min-1) compared with C-BAL (12.2 +/- 1.2 micromol.L-1.kg-1.min-1), and BASE (17.1 +/- 2.2 micromol.L-1.kg-1.min-1), p < 0.05). Fasting fat oxidation was higher in C-DEF than in BASE (109.8 +/- 10.5 vs. 80.7 +/- 9.6 mg.min-1, p < 0.05). In C-DEF, enhanced insulin action was correlated with the magnitude of the carbohydrate deficit (r = 0.82, p < 0.01). Following exercise, re-feeding expended energy, but not carbohydrate, increased fasting fat oxidation, and shifted insulin-mediated glucose disposal toward increased storage and away from oxidation.

Effect of timing of energy and carbohydrate replacement on post-exercise insulin action.

The nutritional environment surrounding an exercise bout modulates post-exercise insulin action. The purpose of this study was to determine how timing energy and carbohydrate replacement proximate to an exercise bout influences exercise-enhanced insulin action. To create an appropriate baseline, sensitivity to insulin was reduced in 9 healthy young men (n=6) and women (n=3) by 2 days of energy surplus and detraining. Then, insulin action (glucose uptake per unit plasma insulin) was assessed by stable isotope dilution during a continuous glucose infusion 12 h after a standardized meal under 4 conditions. In 3 conditions, the meal replaced the energy and carbohydrate expended during an exercise bout (62.9+/-2.8 min cycle ergometry at 65% VO2 peak followed by ten 30 s sprints). The meal was given before (Pre), immediately after (ImmPost), or 3 h after exercise (Delay). The 4th condition was a no-exercise control (Control). Data were analyzed using linear mixed-effects models with planned contrasts. Relative to Control, insulin action increased by 22% in Pre (p=0.05), 44% in ImmPost (p<0.01), and 19% in Delay (p=0.09). Non-oxidative disposal was higher, and oxidative disposal was lower in ImmPost relative to Control and Pre (p<0.05). Hepatic glucose production was suppressed by the infusion to a greater extent in Pre and Delay (76.9%+/-8.8% and 81.2%+/-4.7%) compared with ImmPost (64.7%+/-10.0%). A bout of exercise enhances insulin action even when expended energy and carbohydrate are replaced. Further, timing of energy and carbohydrate consumption subtly modulates the effectiveness of exercise to enhance insulin action.

The influence of biological maturation on fat and carbohydrate metabolism during exercise in males.

This study examined substrate use during exercise in early-pubertal (EP), mid-pubertal (MP), late-pubertal (LP), and young-adult (YA) males. Fuel use was calculated using the RER and VO2 response during cycling exercise at 30 to 70% of VO2speak. Significant group by intensity interactions were found for lactate, RER, percent CHO, and fat use, in addition to fat and CHO oxidation rates, which suggest a maturation effect on substrate use during exercise. While significance was not achieved at all intensities, post hoc analyses revealed greater fat use, lower CHO use, and lower lactate concentrations in EP and MP compared to LP or YA. No differences were noted between EP and MP or LP and YA at any intensity, suggesting the development of an adult-like metabolic profile occurs between mid- to late-puberty and is complete by the end of puberty.