(588) The Relationship between Cystic Fibrosis Transmembrane Conductance Regulator Dysfunction and Impairment in Limb Muscle Contractile Function in Adults with Cystic Fibrosis

Background: Genetic mutations in cystic fibrosis (CF) result in the dysfunction of the CF transmembrane conductance regulator (CFTR) protein. The CFTR protein is expressed in human skeletal muscle. However, its impact on skeletal muscle abnormalities in CF is unknown. As people with CF are living longer, limb muscle impairment becomes more prominent. An understanding of the associations between the severity of CFTR protein dysfunction and the extent of impairment in muscle contractile function will help formulate evidence-based treatment goals to improve the limb muscle contractile function in people with CF. The objectives of this study were to investigate the association between the severity of CFTR protein dysfunction and the degree of impairment in skeletal muscle contractile function in adults with CF.

Methods: This is a prospective, cross-sectional study, comparing quadriceps muscle strength, quadriceps muscle contractility (i.e. quadriceps muscle torque normalized to quadriceps layer thickness), biceps and handgrip strength, and leg muscle power, between adults with CF with minimal vs residual function CFTR mutations (i.e. severe vs mild CFTR protein dysfunction). People were recruited from the Toronto Adult Cystic Fibrosis Centre at St. Michael's Hospital, Unity Health Toronto. Quadriceps muscle torque was measured with a fixed dynamometer, biceps and handgrip forces with handheld dynamometers, and leg muscle power with stair climb power test. Ultrasound images of quadriceps layer thickness were obtained for quadriceps muscle size. Descriptive statistics were computed, using median (range) for continuous variables, and frequency and percentage for categorical variables. Multivariable linear regression models were developed using the purposeful selection technique to adjust for confounders.

Results: Thirty-four adults with minimal and 18 with residual function CFTR mutations participated in this study. People in the minimal group vs residual group were 29 (19-50) vs 42 (22-66) years of age; had a median (range) FEV₁ of 70 (26-104) vs 74 (29-107) % pred.; BMI 22.7 (17.8-29.4) vs 24.4 (19.4-32.4) kg/m²; and 62% vs 44% were male, respectively. People with residual function CFTR mutations had higher quadriceps muscle contractility by 27.5 Nm/cm [95%CI (2.2, 52.8) Nm/cm, p=.034], after adjusting for forced vital capacity (FVC % pred.) and the interaction between FVC and CFTR mutation group. There were no significant differences between the two groups in absolute quadriceps muscle torque (p=.88), biceps force (p=.38), handgrip force (p=.30), or leg muscle power (p=.81).

Conclusions: The association between CFTR protein dysfunction and impairment in muscle contractility suggested a limited capacity to exert muscle force per unit of muscle size in people with CF. Future studies are needed to confirm the results with cellular and molecular studies in humans with CF. Despite lower muscle contractility in the minimal group, we did not find any association between the severity of CFTR protein dysfunction and impairment in quadriceps muscle strength, likely because of the relatively large quadriceps muscle sizes in our study cohort. Exercise programs focusing on muscle hypertrophy may thus help compensate for the impaired muscle contractility in people with CF.

Acknowledgements: This work was supported by the Canadian Lung Association, and KW was supported by fellowships from the Canadian Lung Association, the Lung Health Foundation, the Physiotherapy Foundation of Canada, and the University of Toronto.

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