Physical activity, intensive exercise, and mechanisms for muscle impairment in patients with idiopathic inflammatory myopathies

Idiopathic inflammatory myopathies (IIM), or myositis, are chronic, heterogenous systemic inflammatory diseases, characterized by low muscle strength and muscle endurance as hallmark symptoms. Patients are often left with sustained disability and reduced physical function and quality of life. The cause of the reduced muscle function is yet unknown, and levels of inflammation correlates poorly with muscle strength. Several mechanisms have been proposed, one of them being impaired mitochondrial function leading to reduced work capacity of the muscles. Today, physical exercise is a central adjuvant treatment to combat the disease, however, it is still unknown how these patients can exercise early in the disease to try to avoid the deterioration and maintain function and strength instead of trying to recover it.

The aim of this thesis was threefold; to investigate the role of physical activity on quality of life, anxiety, and depression, to investigate possible mechanisms causing muscle impairment, and to investigate the efficacy on aerobic capacity, and safety regarding disease activity, of high-intensity interval training in recent onset IIM.

Questionnaires on self-reported level of physical activity, anxiety and depression was given to patients, additional data were obtained from the Swedish Rheumatology Quality Registry (SRQ). As much as 82 % of the 246 participants reported sufficient physical activity according to recommendations. Logistic regression models revealed the possible protective role of physical activity on depression with a reduced risk of 77 %, and that for every millimeter increase of fatigue, the risk of anxiety increased by 2 % and for depression by 3 % (Paper I). By incubating muscle from healthy mice with patient sera, a reduced force production across stimulation frequencies was seen after 24 hours of incubation in both 10 % and 50 % serum concentration. There were no negative effects on force production when incubating with sera from healthy controls or isolated IgG from autoantibody positive patients. Further, tetanic [Ca2+] in mechanically isolated muscle fiber was not affected by patient sera. For the first time, patient serum has been demonstrated to induce muscle weakness in mouse skeletal muscle, suggesting non-cellular factors within the systemic circulation may contribute to impaired muscle function in IIM (Paper II). In a randomized controlled multicenter trial, the efficacy and safety of high-intensity interval training was investigated in recent-onset IIM. Participants were randomly allocated, by a blinded person, to either HIIT or control (CON). Clinical assessments, blood test, maximal exercise test, and patient-reported outcomes (e.g., quality of life, pain, and fatigue) were performed at inclusion and 12-week follow-up. HIIT comprised six 30-45-seconds intervals per session with 2 minutes of active rest in- between), with three weekly supervised sessions. CON did a low-to-moderate home-based exercise protocol with eight exercises of ten reps each and a 15- minute-walk, five times weekly. HIIT outperformed CON regarding oxygen uptake (VO2peak), as well as peak power and time-to-exhaustion in the maximal exercise test. Further HIIT had higher levels of mitochondrial proteins at follow-up (Paper III). HIIT did not increase inflammation or disease activity in any measure. It did not outperform CON in improving disease activity, however, HIIT did improve self- reported physical function and general health. Tere were no statistically significant difference between the groups in rating of fatigue or pain. The HIIT group significantly reducing the daily prednisone dosage (Paper IV).

Overall, this thesis highlights the importance of physical activity and patient- reported outcomes. Further, we have demonstrated that non-cellular factors in systemic circulation could impair muscle function, but not autoantibodies or [Ca2+]. Lastly, our results demonstrate that HIIT is more effective in improving aerobic capacity, mitochondrial function and physical function compared to standard home exercise in recent-onset IIM, while not increasing inflammation or disease activity.

List of scientific papers

Papers included in this thesis listed below with roman numerals.

I. Self-reported physical activity and fatigue and its associations to anxiety and depression in adult patients with idiopathic inflammatory myopathies: a MIHRA psychological impact and MIHRA exercise and rehabilitation scientific working groups collaboration. Kristofer M Andreasson, Fabricio Espinosa-Ortega, Helene Sandlund, Helene Alexanderson. Clin Exp Rheumatol. 2024 Sep 10. Epub ahead of print. PMID: 39263797. doi: https://doi.org/10.55563/clinexprheumatol/5u5ah3.

II. Serum from patients with idiopathic inflammatory myopathy induces skeletal muscle weakness. Cecilia Leijding, Suchada Kaewin, Kristofer M Andreasson, Begum Horuluoglu, Angeles Shunashy Galindo-Feria, Eveline Van Gompel, Maryam Dastmalchi, Stefano Gastaldello, Helene Alexanderson, Ingrid E Lundberg, Daniel C Andersson. Ann Rheum Dis. 2024 Nov 14;83(12):1796-1797. PMID: 39197873. doi: https://doi.org/10.1136/ard-2024-225912.

III. High-Intensity Interval Training Outperforms Moderate Exercise to Improve Aerobic Capacity in Patients with Recent-Onset Idiopathic Inflammatory Myopathies: A Multicenter Randomized Controlled Trial. Kristofer M Andreasson, Cecilia Leijding, Maryam Dastmalchi, Antonella Notarnicola, Stefano Gastaldello, Takashi Yamada, Heléne Sandlund, Dag Leonard, Håkan Westerblad, Ingrid E Lundberg, Daniel C Andersson Helene Alexanderson. medRxiv 2024.12.05.24318130; doi: https://doi.org/10.1101/2024.12.05.24318130 [Manuscript Preprint]

IV. High-Intensity Interval Training in Recent-Onset Idiopathic Inflammatory Myopathies Does Not Increase Inflammation but Improves Self-Reported Physical Function: A multicenter randomized controlled trial. Kristofer M Andreasson, Maryam Dastmalchi, Antonella Notarnicola, Helene Sandlund, Dag Leonard, Håkan Westerblad, Daniel C Andersson, Ingrid E Lundberg, Helene Alexanderson. [Manuscript]