Maarten S. Werkman

Exercise oxidative skeletal muscle metabolism in adolescents with cystic fibrosis

What is the central question of this study? Do intrinsic abnormalities in oxygenation and/or muscle oxidative metabolism contribute to exercise intolerance in adolescents with mild cystic fibrosis? What is the main finding and its importance? This study found no evidence that in adolescents with mild cystic fibrosis in a stable clinical state intrinsic abnormalities in skeletal muscle oxidative metabolism seem to play a clinical significant role. Based on these results, we concluded that there is no metabolic constraint to benefit from exercise training.

Chronic inflammation and infection associate with a lower exercise training response in cystic fibrosis adolescents

Considerable heterogeneity among training-induced effects is observed in patients with cystic fibrosis (CF). We previously showed that longitudinal changes in exercise capacity in adolescents with CF were negatively associated with Pseudomonas aeruginosa (P. aeruginosa) colonization and total immunoglobulin G (IgG) levels, independent of age, pulmonary function and bodyweight. This is the first study investigating whether chronic inflammation and infection also associate with the exercise training response in adolescents with CF. Participants performed a home-based exercise training program for 12 weeks. Pulmonary function, anthropometrics, exercise capacity, markers of inflammation and P. aeruginosa colonization status were measured at baseline. Exercise training-induced changes in pulmonary function and exercise capacity were compared between patients with a low and high inflammation-infection status. Participants with CF with high total IgG levels and P. aeruginosa colonization improved significantly less from the exercise training program, with regard to maximal oxygen consumption. These observations support the hypothesis that chronic systemic inflammation and infection leads to devastating effects on skeletal muscles, hampering skeletal muscle tissue to improve from regular physical exercise. Data further suggest that patients with CF should preferentially be encouraged to engage in regular physical exercise when inflammation and infection status is low (e.g. at a young age).

Estimating peak oxygen uptake in adolescents with cystic fibrosis

Objectives To predict peak oxygen uptake (VO2peak) from the peak work rate (Wpeak) obtained during a cycle ergometry test using the Godfrey protocol in adolescents with cystic fibrosis (CF), and assess the accuracy of the model for prognostication clustering. Methods Out of our database of anthropometric, spirometric and maximal exercise data from adolescents with CF (N=363; 140 girls and 223 boys; age 14.77±1.73 years; mean expiratory volume in 1 s (FEV1%pred) 86.82±17.77%), a regression equation was developed to predict VO2peak (mL/min). Afterwards, this prediction model was validated with cardiopulmonary exercise data from another 60 adolescents with CF (28 girls, 32 boys; mean age 14.6±1.67 years; mean FEV1%pred 85.43±20.01%). Results We developed a regression model VO2peak (mL/min)=216.3–138.7×sex (0=male; 1=female)+11.5×Wpeak; R2=0.91; SE of the estimate (SEE) 172.57. A statistically significant difference (107 mL/min; p<0.001) was found between predicted VO2peak and measured VO2peak in the validation group. However, this difference was not clinically relevant because the difference was within the SEE of the model. Furthermore, we found high positive predictive and negative predictive values for the model for prognostication clustering (PPV 50–87% vs NPV 82–94%). Conclusions In the absence of direct VO2peak assessment it is possible to estimate VO2peak in adolescents with CF using only a cycle ergometer. Furthermore, the regression model showed to be able to discriminate patients in different prognosis clusters based on exercise capacity.

Validity of the Pediatric Running-Based Anaerobic Sprint Test to Determine Anaerobic Performance in Healthy Children.

PURPOSE To determine criterion validity of the pediatric running-based anaerobic sprint test (RAST) as a nonsophisticated field test for evaluating anaerobic performance in healthy children and adolescents. METHODS Data from 65 healthy children (28 boys and 37 girls between 6 and 18 years of age, mean ± SD age: 10.0 ± 2.8 years) who completed both the pediatric RAST and the 30-s Wingate anaerobic test (WAnT) on a cycle ergometer in a randomized order were analyzed. Peak power (PP) and mean power (MP) were the primary outcome measures for both tests. RESULTS There were no significant sex-differences in PP and MP attained at the pediatric RAST and the WAnT. Age was strongly correlated to pediatric RAST and WAnT performance (Spearmans rho values ranging from 0.85 to 0.90, with p < .001 for all coefficients). We found high correlation coefficients between pediatric RAST performance and WAnT performance for both PP (Spearmans rho: 0.86; p < .001) and MP (Spearmans rho: 0.91; p < .001). CONCLUSION The pediatric RAST can be used as a valid and nonsophisticated field test for the assessment of anaerobic performance in healthy children and adolescents. For clinical evaluative purposes, we suggest to use MP of the pediatric RAST when assessing glycolytic power in the absence of the WAnT.

Development of a framework to describe goals and content of exercise interventions in physical therapy: a mixed method approach including a systematic review

Abstract Background: Exercise interventions in physical therapy (PT) are often not well described in research reports. Omitting details of the intervention hampers the transfer to daily clinical practice. Objective: To develop a framework for describing goals and content of exercise interventions, in order to provide structured and detailed information for use in research reports. Methods: A framework was developed in three steps using a mixed method approach. First, the scientific literature was systematically searched for available methods to describe PT interventions. An inventory of these methods was made and relevant elements were extracted. Second, based on the results of the literature search, a global framework was developed by a focus group of experts in the field of PT. Third, the framework was field tested by describing four different exercise interventions, leading to a final version. Results: In the developed framework intervention goals at the level of body functions and activities/participation were listed using the International Classification of Functioning, Disability and Health. To guide the description of the content of the exercise intervention a list of intervention details was developed, which was derived from an existing classification of PT interventions. Goals and content of exercise interventions were linked. Field testing of the framework led to adequate descriptions of exercise interventions. Conclusion: The developed framework is a promising first step in offering a feasible guide for a structured and detailed description of goals and content of exercise interventions within research reports.

A Possible Alternative Exercise Test for Youths with Cystic Fibrosis: The Steep Ramp Test

PURPOSE The steep ramp test (SRT) can be used to provide an indication of exercise capacity when gas exchange measurements are not possible. This study evaluated the clinical usefulness of the SRT in adolescents with cystic fibrosis (CF) and compared the physiological responses of the SRT with the standard cardiopulmonary exercise test (CPET). METHODS Forty patients with CF (17 boys and 23 girls; mean ± SD age, 14.7 ± 1.7 years; forced expiratory volume in 1 s, 86% ± 18% of predicted) performed an SRT and a CPET with respiratory gas analysis in a randomized balanced design. Peak work rate (WRpeak), HRpeak, peak minute ventilation (V˙Epeak), and peak oxygen uptake (V˙O2peak) were the main outcome measures. RESULTS Patients with CF attained values for absolute and relative WRpeak during the SRT of 82% ± 14% and 92% ± 14% of predicted. Nutritional status and degree of airway obstruction did not influence SRT performance. Significantly higher values were attained for WRpeak during the SRT compared with those during the CPET (252 ± 60 vs 174 ± 46 W; P < 0.001), whereas significantly lower values were achieved for HRpeak (168 ± 14 vs 182 ± 12 bpm; P < 0.001), V˙Epeak (59.2 ± 19.5 vs 72.0 ± 20.2 L·min(-1); P = 0.006), and V˙O2peak (36.9 ± 7.5 vs 41.5 ± 7.6 mL·kg(-1)·min(-1); P = 0.008). A strong correlation between WRpeak attained at the SRT and the V˙O2peak achieved during the CPET was found (r = 0.822, P < 0.001). CONCLUSIONS The SRT seems to be a quick, convenient, and low-cost exercise test that is well-tolerated in patients with CF with mild-to-moderate airway obstruction. It provides an indication of exercise capacity and can potentially be used when exercise testing using gas exchange measurements is not possible.

Supra-maximal verification of peak oxygen uptake in adolescents with cystic fibrosis

Purpose: To study whether peak oxygen uptake (V . O2 peak), attained in traditional cardiopulmonary exercise testing (CPET) in adolescents with cystic fibrosis (CF), could be verified by a supramaximal exercise test. Methods: Sixteen adolescents with CF (forced expiratory volume in 1 second as % of predicted [range, 45%-117%]) volunteered and successively performed CPET and a supramaximal test (Steep Ramp Test [SRT] protocol). Results: Cardiopulmonary exercise testing and the SRT resulted in comparable cardiorespiratory peak values. We found no significant difference in oxygen uptake (V . O2 peak/kg) between CPET and the SRT (38.9 ± 7.4 and 38.8 ± 8.5 mL min−1 kg−1, respectively; P = .81). We found no systemic bias for CPET and SRT measurements of V . O2 peak/kg and no differences between CPET and SRT V . O2 peak values within and between the maximal and non-maximal effort groups (P > .4). Conclusion: The V . O2 peak measured in CPET seems to reflect the true V . O2 peak in adolescents with CF. (Pediatr Phys Ther 2011;23:15–21)

Rebuttal from Erik H. J. Hulzebos, Jeroen A. L. Jeneson, Cornelis K. van der Ent, Maarten S. Werkman and Tim Takken

Rodriguez-Miguelez and coworkers effectively contend that skeletal muscle oxidative capacity is altered in cystic fibrosis (CF) patients (Rodriguez-Miguelez et al. 2017), based only on past results of in vitro studies in cultured cells and their own in vivo observations in skeletal muscle in CF patients (Erickson et al. 2015). In contrast to what Rodriguez-Miguelez and coworkers claim in their case argument in this CrossTalk discussion (Rodriguez-Miguelez et al. 2017), observations in the three cited ‘corroborating’ in vivo studies of oxidative metabolism in CF skeletal muscle (de Meer et al. 1995; Wells et al. 2011; Erickson et al. 2015) do not support their hypothesis. First, it is important to accept that near infrared spectroscopy (NIRS) measurements of oxidative capacity in skeletal muscles cannot distinguish between a lower mitochondrial number and/or a decline in mitochondrial function (Erickson et al. 2015). Additionally, adipose tissue thickness (> 2 cm) will impede NIRS light penetration, which limits this method to non-obese populations (Erickson et al. 2015). Second, de Meer et al. only reported altered muscle energy balance during dynamic exercise in CF patients compared to healthy controls (de Meer et al. 1995). Post-exercise phosphocreatine (PCr) recovery kinetics reporting independently on mitochondrial function (Meyer, 1988) were, however, not determined (de Meer et al. 1995). Therefore it was not established whether a reduction in oxidative capacity or contractile efficiency contributed to altered muscle energy balance during exercise. Recently, we reported a similar observation of altered muscle energy balance during dynamic exercise in patients with a fatty acid oxidation disorder (Diekman et al. 2016). In that study, however, the underlying cause was not failing mitochondrial function; rather, it may be explained by a slow-to-fast shift in quadriceps fibre-type composition. The measured rates of PCr and Pi recovery post-exercise showed that the mitochondrial capacity for ATP synthesis in the quadriceps muscle was normal (Diekman et al. 2016). With respect to the cited corroborating study by Wells and coworkers, the data show that post-exercise in vivo phosphocreatine recovery kinetics in skeletal muscle of CF patients were, in fact, unchanged from healthy controls in two out of three exercise tests (Wells et al. 2011). Therefore, on the basis of the outcome of that study alone, the hypothesis that oxidative capacity of skeletal muscle in CF is altered has already been rejected (Popper, 1934), because a primary intrinsic defect should always be present, not just in 1 out of 3 tests. Furthermore, our recent report of a normal oxidative capacity of leg muscles in adolescents with CF (Werkman et al. 2016) was corroborated independently by the findings reported by Decorte and coworkers (Gruet et al. 2016; Decorte et al. 2017). They found similar in vivo metabolic skeletal muscle responses during exercise and recovery in adults with CF and healthy controls, and confirm the hypothesis that an altered oxidative capacity in patients with CF is untenable. In conclusion, three in vivo studies verified a normal oxidative capacity of leg muscles in clinically stable (i.e. without any signs of systemic inflammation and/or chronic Pseudomonas aeruginosa colonization) patients with CF (Gruet et al. 2016; Werkman et al. 2016; Decorte et al. 2017). Overall, muscle anabolism rather than specific metabolic dysfunction may be critical regarding muscle function in CF. Further longitudinal studies could be performed aiming to describe the effects of chronic infection and inflammation on muscular function and training. Call for comments

Mechanisms of Exercise Limitation in Cystic Fibrosis: A Literature Update of Involved Mechanisms

Abstract Patients with Cystic Fibrosis (CF) are known to have a reduced exercise tolerance. To date, however, there is no (scientific) consensus about the exact physiological mechanisms leading to a reduced exercise capacity in these patients, and to what extent each mechanism contributes to exercise limitation. Moreover, it is still unknown at which point of the disease process the different exercise-limiting mechanisms come into play. An up-to-date (literature) overview of the determinants known to play a role in the reduced exercise capacity might be helpful for (1) understanding the underlying (physiological) mechanisms, and (2) for providing and indicating appropriate therapeutic interventions such as exercise training in patients with CF.