CrossTalk opposing view: Skeletal muscle oxidative capacity is not altered in cystic fibrosis patients

Exercise has many positive effects on various health outcomes in cystic fibrosis (CF). Higher levels of physical fitness are associated with better quality of life (Hebestreit et al. 2014) and improved survival in this population (Pianosi et al. 2005; Hulzebos et al. 2014). Although exercise intolerance is a hallmark of CF disease, the exact underlying mechanisms remain to be elucidated. It is acknowledged that decrease of pulmonary function alone is insufficient to explain exercise intolerance in patients with CF, especially in patients with mild to moderate lung disease (Dodd et al. 2005). In the literature there is controversy as to whether limb muscle function also has a role in the functional limitations experienced by subjects with CF. The quadriceps femoris muscle has been studied most frequently and has an important role in locomotion. Some studies demonstrated a reduction in maximal muscle strength that correlated with decreased exercise tolerance in both children and adults with CF (de Meer et al. 1999; Sahlberg et al. 2005; Troosters et al. 2009). This muscle weakness has been (traditionally) explained by physical inactivity and altered nutritional status (de Meer et al. 1999). However, in a large sample of subjects with CF, skeletal muscle force impairment was in excess of that expected from physical inactivity alone (Troosters et al. 2009). Moreover, 6 months of endurance and/or resistance training failed to improve muscle strength despite a normal nutritional status (Sahlberg et al. 2008), questioning skeletal muscle trainability in subjects with CF. Thus, the hypothesis of CF-specific impairments in skeletal muscles has been raised. Phosphorus magnetic resonance spectroscopy (31P-MRS) is a powerful non-invasive method to assess muscle metabolism in vivo, both at rest and during exercise, by focusing on changes in concentrations of high-energy phosphate metabolites such as adenosine triphosphate (ATP), creatine phosphate (PCr) and inorganic phosphate (Pi) (van Brussel et al. 2015). de Meer et al. (1995) and Selvadurai et al. (2003) independently reported evidence for altered oxidative metabolism and pH homeostasis during maximal voluntary isometric muscle force, in adolescents with CF. Wells et al. (2011) reported a decreased concentration of PCr, a key myocellular short-term ATP buffer, in resting thigh muscle of 20 children with CF as compared to both 20 healthy controls and 10 patients with primary ciliary dyskinesia, matched for age and physical activity levels. However, subjects with CF achieved the same work rates during a 30 s, 90 s and 5 min exercise test as healthy subjects and primary ciliary dyskinesia patients (Selvadurai et al. 2003), suggesting any potential intrinsic alterations in oxidative capacity to be clinically irrelevant. Furthermore the rate of PCr resynthesis following exercise was found to be normal in two out of the three tests indicating intact mitochondrial ATP synthetic function in the subjects with CF (Meyer, 1988). Indeed, two recent in vivo 31P-MRS studies also failed to find any evidence for impaired mitochondrial function in subjects with CF (Werkman et al. 2016; Decorte et al. 2017). Werkman et al. (2016) found no differences between adolescent subjects with CF and age-, gender- and habitual physical activity-matched healthy controls with regard to resting quadriceps PCr concentration, the magnitude of changes in quadriceps PCr, Pi and pH during in-magnet bicycle exercise, or post-exercise recovery kinetics of PCr and Pi, respectively. Decorte et al. (2017) reported identical findings during voluntary isometric muscle force of the calf muscle of 15 adult subjects with CF. Together, these results point to normal metabolic constraints and normal muscle oxidative metabolism in patients with mild CF and stable clinical condition (i.e. without signs of systemic inflammation and/or chronic Pseudomonas aeruginosa colonization). If not mitochondrial function, what other aspect of muscle physiology may be altered instead in CF impacting contractile function? Lamhonwah et al. (2010) demonstrated that the CFTR protein – which is defective in CF – is expressed at the sarcoplasmic reticulum of human skeletal muscle. They speculated that, as a result, any decreased function of sarcoplasmic reticulum CFTR in CF could lead to dysregulation of Ca2+ homeostasis and muscle weakness. Divangahi et al. (2009) indeed showed reduced expression of CFTR protein and elevated intracellular calcium levels in skeletal muscle cells in a murine model of CF, but also increased inflammatory responses during pulmonary infections leading to excessive muscle wasting. That muscle wasting in patients with advanced CF can play a role is also supported by the study of Gruet et al. (2016). They found in subjects with CF that skeletal muscle endurance, fatigability and quadriceps strength can be explained by the reduced cross-sectional muscle area (Gruet et al. 2016; Stein et al. 2016). Matching subjects with CF compared to age-, gender- and intensity level of (habitual) physical activity-matched healthy controls and using both volitional and non-volitional neuromuscular assessments is critical when comparing muscle function and metabolic abnormalities, because previously reported differences in muscle function in CF could be attributed, at least in part, to muscle deconditioning rather than specific CF muscle dysfunction. Many factors may potentially contribute to reduced muscle mass in CF, such as inflammation (Dufresne et al. 2009; van de Weert-van Leeuwen et al. 2014), medication (Barry & Gallagher, 2003), repeated exacerbations (Burtin et al. 2013), altered nutritional status (de Meer et al. 1999) and/or less engagement in intense activities (Nixon et al. 2001; Troosters et al. 2009). We conclude that children and adults with CF with mild to moderate lung disease have similar muscle function (metabolism, endurance and fatigability) to healthy controls (Gruet et al. 2016; Werkman et al. 2016; Decorte et al. 2017). In active patients with mild to moderate CF, normal phosphorous metabolite degradation and preserved oxidative capacity in limb skeletal muscles have been described (Werkman et al. 2016; Decorte et al. 2017). In patients with reduced muscle performance, decreased muscle mass rather than metabolic dysfunction appears to be an underlying cause (de Meer et al. 1995; Selvadurai et al. 2003; Wells et al. 2011). In these patients reduced muscle contractility does not persist when normalized to muscle cross-sectional area (Gruet et al. 2016; Stein et al. 2016). On this basis, we suggest that small quantitative (reduced muscle mass) rather than qualitative (intrinsic skeletal muscle abnormalities) deficits in subjects with CF may underlie any reduced absolute exercise capacity in patients. Readers are invited to give their views on this and the accompanying CrossTalk articles in this issue by submitting a brief (250 word) comment. Comments may be submitted up to 6 weeks after publication of the article, at which point the discussion will close and the CrossTalk authors will be invited to submit a ‘LastWord’. Please email your comment, including a title and a declaration of interest, to jphysiol@physoc.org. Comments will be moderated and accepted comments will be published online only as ‘supporting information’ to the original debate articles once discussion has closed. H. J. (Erik) Hulzebos is a clinical exercise physiologist and sports physical therapist and assistant professor in clinical health sciences at the University Children's Hospital of the University Medical Center Utrecht, the Netherlands. He received a PT bachelor degree at the University of Applied Science in Utrecht in 1991, an MSc in Exercise Physiology from the Faculty of Health Sciences of the University Maastricht in 1998 and a PhD from the Faculty of Medicine of Utrecht University in 2006. His main research and clinical interest is clinical (paediatric) exercise physiology. He has performed studies on many clinical populations including children and adults with cardiorespiratory disease. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. None declared.