Skeletal Muscle Weakness: A Novel Treatable Trait in Asthma?

Abstract

Many patients with moderate-to-severe asthma are symptomatic and have exacerbations and limitations in their daily activities.1Global Strategy for Asthma Management and PreventionGlobal Initiative for Asthma (GINA); 2022.https://www.ginasthma.org/Date accessed: May 22, 2022Google Scholar The Global Initiative for Asthma (GINA) report1Global Strategy for Asthma Management and PreventionGlobal Initiative for Asthma (GINA); 2022.https://www.ginasthma.org/Date accessed: May 22, 2022Google Scholar advises us to consider the pharmacotherapy and several nonpharmacological means such as allergen avoidance, smoking cessation, and avoidance of occupational exposures or medications that may worsen asthma.1Global Strategy for Asthma Management and PreventionGlobal Initiative for Asthma (GINA); 2022.https://www.ginasthma.org/Date accessed: May 22, 2022Google Scholar But have you ever considered that you should worry about the skeletal muscle of our patient with asthma? Visser et al2Visser E. de Jong K. van Zutphen T. Kerstjens H.A.M. ten Brinke A. Muscle function in moderate to severe asthma: association with clinical outcomes and inflammatory marker.J Allergy Clin Immunol Pract. 2023; 11: 1439-1447Google Scholar evaluated skeletal muscle mass and strength in a group of patients with moderate-to-severe asthma and evaluated their association with asthma outcomes such as pulmonary function, 6-minute walking distance (6MWD), asthma control, quality of life, and health care use. Muscle mass was estimated by fat-free mass index (FFMI) as evaluated by whole-body bioelectrical impedance analysis and urinary creatinine excretion rate (CER). Creatinine excretion in a 24-hour urine sample is a marker of total muscle mass with higher values indicating higher total muscle mass. Furthermore, they assessed muscle strength by measuring hand grip strength (HGS). A low value was considered when it was below the 10th percentile of age- and sex-adjusted values for general population.2Visser E. de Jong K. van Zutphen T. Kerstjens H.A.M. ten Brinke A. Muscle function in moderate to severe asthma: association with clinical outcomes and inflammatory marker.J Allergy Clin Immunol Pract. 2023; 11: 1439-1447Google Scholar First, they found that among patients with GINA 3-5 asthma, 16% had a low FFMI, 8% had a low CER, and 5% had a low HGS, indicating that low FFMI might be more common in asthma than in the general population.2Visser E. de Jong K. van Zutphen T. Kerstjens H.A.M. ten Brinke A. Muscle function in moderate to severe asthma: association with clinical outcomes and inflammatory marker.J Allergy Clin Immunol Pract. 2023; 11: 1439-1447Google Scholar This is supported by other studies showing that in patients with severe refractory asthma, FFMI is at the same level as in patients with stage IV chronic obstructive pulmonary disease (COPD)3Minas M. Papaioannou A.I. Tsaroucha A. Daniil Z. Hatzoglou C. Sgantzos M. et al.Body composition in severe refractory asthma: comparison with COPD patients and healthy smokers.PLoS One. 2010; 5: e13233Crossref Scopus (14) Google Scholar and that patients with uncontrolled asthma have increased fat mass and decreased muscle mass compared with patients with controlled asthma or healthy controls.4Abdo M. Waschki B. Kirsten A.-M. Trinkmann F. Biller H. Herzmann C. et al.Persistent uncontrolled asthma: long-term impact on physical activity and body composition.J Asthma Allergy. 2021; 14: 229-240Crossref PubMed Scopus (11) Google Scholar Thus, evidence is accumulating that decreased skeletal muscle mass is present in at least some of our patients with moderate-to-severe and/or uncontrolled asthma. In the study of Visser et al,2Visser E. de Jong K. van Zutphen T. Kerstjens H.A.M. ten Brinke A. Muscle function in moderate to severe asthma: association with clinical outcomes and inflammatory marker.J Allergy Clin Immunol Pract. 2023; 11: 1439-1447Google Scholar both lower FFMI and CER were associated with lower values of forced expiratory volume in 1 second (FEV1) and 6MWD, whereas a lower HGS was related to worse asthma control, poorer quality of life, and a higher probability of emergency visits. The differences can be considered clinically relevant as the postbronchodilator FEV1 predicted was 86% in the lowest FFMI tertile and 99% to 102% in the higher tertiles.2Visser E. de Jong K. van Zutphen T. Kerstjens H.A.M. ten Brinke A. Muscle function in moderate to severe asthma: association with clinical outcomes and inflammatory marker.J Allergy Clin Immunol Pract. 2023; 11: 1439-1447Google Scholar Similarly, in the lowest HGS tertile, 67% had ≥1 emergency visit in preceding year, whereas the percentage was clearly lower (38%-40%) in the 2 higher HGS tertiles.2Visser E. de Jong K. van Zutphen T. Kerstjens H.A.M. ten Brinke A. Muscle function in moderate to severe asthma: association with clinical outcomes and inflammatory marker.J Allergy Clin Immunol Pract. 2023; 11: 1439-1447Google Scholar Muscle loss and/or weakness is considered as a part of a syndrome called frailty. The results of Visser et al2Visser E. de Jong K. van Zutphen T. Kerstjens H.A.M. ten Brinke A. Muscle function in moderate to severe asthma: association with clinical outcomes and inflammatory marker.J Allergy Clin Immunol Pract. 2023; 11: 1439-1447Google Scholar are supported by a recent study from Japan evaluating frailty and muscle weakness in elderly patients with asthma.5Ryu K. Fukutomi Y. Nakatani E. Iwata E. Iwata M. Nagayama K. et al.Frailty and muscle weakness in elderly patients with asthma their association with cumulative lifetime oral corticosteroid exposure.Allergol Int. 2023; 72: 252-261Crossref Scopus (2) Google Scholar They report that lung function is lower in patients with asthma identified as being frail. Furthermore, an association between lower lung function, lean mass index, and HGS was found.5Ryu K. Fukutomi Y. Nakatani E. Iwata E. Iwata M. Nagayama K. et al.Frailty and muscle weakness in elderly patients with asthma their association with cumulative lifetime oral corticosteroid exposure.Allergol Int. 2023; 72: 252-261Crossref Scopus (2) Google Scholar What is the reason behind reduced FFMI and/or skeletal muscle strength in moderate-to-severe2Visser E. de Jong K. van Zutphen T. Kerstjens H.A.M. ten Brinke A. Muscle function in moderate to severe asthma: association with clinical outcomes and inflammatory marker.J Allergy Clin Immunol Pract. 2023; 11: 1439-1447Google Scholar or uncontrolled4Abdo M. Waschki B. Kirsten A.-M. Trinkmann F. Biller H. Herzmann C. et al.Persistent uncontrolled asthma: long-term impact on physical activity and body composition.J Asthma Allergy. 2021; 14: 229-240Crossref PubMed Scopus (11) Google Scholar asthma? Three possible pathways emerge: (1) corticosteroid-induced myopathy, (2) systemic inflammation resembling that present in COPD,6Dalle S. Koppo K. Is inflammatory signaling involved in disease-related muscle wasting? Evidence from osteoarthritis, chronic obstructive pulmonary disease and type II diabetes.Exp Gerontol. 2020; 137: 110964Crossref PubMed Scopus (23) Google Scholar and (3) physical inactivity. The features of corticosteroid-induced myopathy include muscle wasting, weakness, and/or fatigability affecting respiratory and/or limb muscles.7Wu K. Michalski A. Cortes D. Rozenberg D. Mathur S. Glucocorticoid-induced myopathy in people with asthma: a systematic review.J Asthma. 2022; 59: 1396-1409Crossref Scopus (6) Google Scholar A recent meta-analysis reported inconsistent results on glucocorticoid-induced myopathy in asthma.7Wu K. Michalski A. Cortes D. Rozenberg D. Mathur S. Glucocorticoid-induced myopathy in people with asthma: a systematic review.J Asthma. 2022; 59: 1396-1409Crossref Scopus (6) Google Scholar However, life-long oral corticosteroid (OCS) exposure was clearly associated with frailty in asthma,5Ryu K. Fukutomi Y. Nakatani E. Iwata E. Iwata M. Nagayama K. et al.Frailty and muscle weakness in elderly patients with asthma their association with cumulative lifetime oral corticosteroid exposure.Allergol Int. 2023; 72: 252-261Crossref Scopus (2) Google Scholar and OCS and inhaled corticosteroid use were found as significant predictors of muscle mass and fat mass in asthma.4Abdo M. Waschki B. Kirsten A.-M. Trinkmann F. Biller H. Herzmann C. et al.Persistent uncontrolled asthma: long-term impact on physical activity and body composition.J Asthma Allergy. 2021; 14: 229-240Crossref PubMed Scopus (11) Google Scholar Thus, we cannot exclude the possibility that part of the reduced muscle mass and strength is related to exposure to corticosteroids. In COPD and in the frailty syndrome, systemic inflammation and/or oxidative stress are considered as mechanisms leading to muscle wasting.6Dalle S. Koppo K. Is inflammatory signaling involved in disease-related muscle wasting? Evidence from osteoarthritis, chronic obstructive pulmonary disease and type II diabetes.Exp Gerontol. 2020; 137: 110964Crossref PubMed Scopus (23) Google Scholar,8Qaisar R. Qayum M. Muhammad T. Reduced sarcoplasmic reticulum Ca2+ ATPase activity underlies skeletal muscle wasting in asthma.Life Sci. 2021; 273: 119296Crossref PubMed Scopus (14) Google Scholar Visser et al2Visser E. de Jong K. van Zutphen T. Kerstjens H.A.M. ten Brinke A. Muscle function in moderate to severe asthma: association with clinical outcomes and inflammatory marker.J Allergy Clin Immunol Pract. 2023; 11: 1439-1447Google Scholar did not find associations between systemic inflammatory markers and muscle function, except between FFMI and leukocyte count. However, this result may be hampered by the small sample size.2Visser E. de Jong K. van Zutphen T. Kerstjens H.A.M. ten Brinke A. Muscle function in moderate to severe asthma: association with clinical outcomes and inflammatory marker.J Allergy Clin Immunol Pract. 2023; 11: 1439-1447Google Scholar A recent study proposed that muscle weakness and atrophy in asthma are partly driven by skeletal muscle sarcoplasmic reticulum Ca2+ ATPase dysfunction and oxidative stress.8Qaisar R. Qayum M. Muhammad T. Reduced sarcoplasmic reticulum Ca2+ ATPase activity underlies skeletal muscle wasting in asthma.Life Sci. 2021; 273: 119296Crossref PubMed Scopus (14) Google Scholar The third option is that muscle weakness and atrophy are due to a low level of physical activity. To clarify, physical activity is defined as “any bodily movement produced by skeletal muscles that requires energy expenditure.”9Loponen J. Ilmarinen P. Tuomisto L.E. Niemelä O. Tommola M. Nieminen P. et al.Daily physical activity and lung function decline in adult-onset asthma: a 12-year follow-up study.Eur Clin Respir J. 2018; 5: 1533753Crossref PubMed Scopus (21) Google Scholar Among patients with asthma, both males and females having lowest muscle mass had the lowest number of daily steps and time spent with moderate physical activity.4Abdo M. Waschki B. Kirsten A.-M. Trinkmann F. Biller H. Herzmann C. et al.Persistent uncontrolled asthma: long-term impact on physical activity and body composition.J Asthma Allergy. 2021; 14: 229-240Crossref PubMed Scopus (11) Google Scholar Asthma control and physical activity were found as independent predictors of body composition evaluated as skeletal muscle mass or fat mass.4Abdo M. Waschki B. Kirsten A.-M. Trinkmann F. Biller H. Herzmann C. et al.Persistent uncontrolled asthma: long-term impact on physical activity and body composition.J Asthma Allergy. 2021; 14: 229-240Crossref PubMed Scopus (11) Google Scholar Furthermore, in follow-up, it was found that despite stable body mass index, patients with persistent uncontrolled asthma had reduced physical activity, and it was associated with loss of skeletal muscle mass and an increase in fat mass. Similar changes were not found in patients having controlled asthma and higher physical activity.4Abdo M. Waschki B. Kirsten A.-M. Trinkmann F. Biller H. Herzmann C. et al.Persistent uncontrolled asthma: long-term impact on physical activity and body composition.J Asthma Allergy. 2021; 14: 229-240Crossref PubMed Scopus (11) Google Scholar In a study with patients having adult-onset asthma and similar characteristics as the patients in the study of Visser et al,2Visser E. de Jong K. van Zutphen T. Kerstjens H.A.M. ten Brinke A. Muscle function in moderate to severe asthma: association with clinical outcomes and inflammatory marker.J Allergy Clin Immunol Pract. 2023; 11: 1439-1447Google Scholar it was found that 37% of patients had very low levels of physical activity, around 1.5 to 3 hours per day, a level that corresponds to elderly care home residents.9Loponen J. Ilmarinen P. Tuomisto L.E. Niemelä O. Tommola M. Nieminen P. et al.Daily physical activity and lung function decline in adult-onset asthma: a 12-year follow-up study.Eur Clin Respir J. 2018; 5: 1533753Crossref PubMed Scopus (21) Google Scholar Patients with a low level of physical activity had a faster decline in lung function in the long term as compared with those having a higher level of physical activity.9Loponen J. Ilmarinen P. Tuomisto L.E. Niemelä O. Tommola M. Nieminen P. et al.Daily physical activity and lung function decline in adult-onset asthma: a 12-year follow-up study.Eur Clin Respir J. 2018; 5: 1533753Crossref PubMed Scopus (21) Google Scholar This is well in line with the results of Visser et al2Visser E. de Jong K. van Zutphen T. Kerstjens H.A.M. ten Brinke A. Muscle function in moderate to severe asthma: association with clinical outcomes and inflammatory marker.J Allergy Clin Immunol Pract. 2023; 11: 1439-1447Google Scholar and Abdo et al,4Abdo M. Waschki B. Kirsten A.-M. Trinkmann F. Biller H. Herzmann C. et al.Persistent uncontrolled asthma: long-term impact on physical activity and body composition.J Asthma Allergy. 2021; 14: 229-240Crossref PubMed Scopus (11) Google Scholar suggesting that there may exist a vicious circle between low physical activity, reduced muscle mass, and reduced lung function. In fact, a similar vicious circle has been proposed among patients with COPD.10Global Initiative for Chronic Obstructive Lung DiseaseGlobal strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2023 report).http://www.copdgold.comDate accessed: November 16, 2022Google Scholar Recently, a concept of treatable traits has become popular in obstructive lung diseases. Instead of prescribing similar therapy to all patients, individual features of the patient and disease should be identified and treatment should be targeted to these. The study of Visser et al2Visser E. de Jong K. van Zutphen T. Kerstjens H.A.M. ten Brinke A. Muscle function in moderate to severe asthma: association with clinical outcomes and inflammatory marker.J Allergy Clin Immunol Pract. 2023; 11: 1439-1447Google Scholar showed that low FFMI or skeletal muscle weakness is associated with lower lung function, poorer asthma control and quality of life, and a greater likelihood of emergency visits. In contrast, FFMI or skeletal muscle weakness was not associated with asthma severity or inflammation markers such as fractional exhaled nitric oxide or blood eosinophils.2Visser E. de Jong K. van Zutphen T. Kerstjens H.A.M. ten Brinke A. Muscle function in moderate to severe asthma: association with clinical outcomes and inflammatory marker.J Allergy Clin Immunol Pract. 2023; 11: 1439-1447Google Scholar,5Ryu K. Fukutomi Y. Nakatani E. Iwata E. Iwata M. Nagayama K. et al.Frailty and muscle weakness in elderly patients with asthma their association with cumulative lifetime oral corticosteroid exposure.Allergol Int. 2023; 72: 252-261Crossref Scopus (2) Google Scholar This suggests that low FFMI and/or skeletal muscle weakness is a trait separate from asthma severity or inflammation markers. Is it treatable? β2-Agonists are used to relieve bronchospasm in asthma but are also powerful anabolic agents triggering skeletal muscle hypertrophy.11Joassar O.R. Durieux A.-C. Freyssenet D.G. β2-Adrenergic agonists and the treatment of skeletal muscle wasting disorders.Int J Biochem Cell Biol. 2013; 45: 2309-2321Crossref Scopus (57) Google Scholar However, the currently used doses of inhaled β2-agonists do not significantly increase skeletal muscle mass or strength in obstructive diseases.11Joassar O.R. Durieux A.-C. Freyssenet D.G. β2-Adrenergic agonists and the treatment of skeletal muscle wasting disorders.Int J Biochem Cell Biol. 2013; 45: 2309-2321Crossref Scopus (57) Google Scholar This leaves us the other option, that is, physical activity and exercise as ways to increase muscle mass and strength. In COPD, there is a huge interest in implementing behavior-targeted interventions to improve physical activity and to reverse the downward spiral of inactivity that predisposes patients to reduced quality of life, increased rates of hospitalization, and mortality.10Global Initiative for Chronic Obstructive Lung DiseaseGlobal strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2023 report).http://www.copdgold.comDate accessed: November 16, 2022Google Scholar Physical activity and pulmonary rehabilitation are considered central parts of nonpharmacological therapy of COPD.10Global Initiative for Chronic Obstructive Lung DiseaseGlobal strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2023 report).http://www.copdgold.comDate accessed: November 16, 2022Google Scholar In asthma, regular physical activity is recommended but for its general health benefits and to tolerate exercise-induced bronchoconstriction.1Global Strategy for Asthma Management and PreventionGlobal Initiative for Asthma (GINA); 2022.https://www.ginasthma.org/Date accessed: May 22, 2022Google Scholar However, the recent results2Visser E. de Jong K. van Zutphen T. Kerstjens H.A.M. ten Brinke A. Muscle function in moderate to severe asthma: association with clinical outcomes and inflammatory marker.J Allergy Clin Immunol Pract. 2023; 11: 1439-1447Google Scholar, 3Minas M. Papaioannou A.I. Tsaroucha A. Daniil Z. Hatzoglou C. Sgantzos M. et al.Body composition in severe refractory asthma: comparison with COPD patients and healthy smokers.PLoS One. 2010; 5: e13233Crossref Scopus (14) Google Scholar, 4Abdo M. Waschki B. Kirsten A.-M. Trinkmann F. Biller H. Herzmann C. et al.Persistent uncontrolled asthma: long-term impact on physical activity and body composition.J Asthma Allergy. 2021; 14: 229-240Crossref PubMed Scopus (11) Google Scholar, 5Ryu K. Fukutomi Y. Nakatani E. Iwata E. Iwata M. Nagayama K. et al.Frailty and muscle weakness in elderly patients with asthma their association with cumulative lifetime oral corticosteroid exposure.Allergol Int. 2023; 72: 252-261Crossref Scopus (2) Google Scholar,9Loponen J. Ilmarinen P. Tuomisto L.E. Niemelä O. Tommola M. Nieminen P. et al.Daily physical activity and lung function decline in adult-onset asthma: a 12-year follow-up study.Eur Clin Respir J. 2018; 5: 1533753Crossref PubMed Scopus (21) Google Scholar offer a completely different reason to recommend physical activity: to maintain skeletal muscle mass and strength to prevent lung function loss, improve asthma control and quality of life, and prevent exacerbations. These results encourage longitudinal studies into muscle function as a novel treatable trait to improve asthma outcomes. So, what is the message to our clinical practice? In a patient with asthma and poor lung function, high symptom burden or exacerbations, low skeletal muscle mass, and strength may contribute to the poor asthma outcome. These can be evaluated, for example, by measuring FFMI or HGS. Especially in the case of poor values, the patient should be instructed to increase the amount of regular physical activity/exercise to gain muscle mass and strength, and maybe referred to regular exercise or rehabilitation. Muscle Function in Moderate to Severe Asthma: Association With Clinical Outcomes and Inflammatory MarkersThe Journal of Allergy and Clinical Immunology: In PracticeVol. 11Issue 5PreviewPatients with severe asthma have been shown to have low muscle mass, but the clinical consequences are unknown. Full-Text PDF Open Access