Periodic Reporting for period 1 - COPD-HIT (Innovative treatment for extrapulmonary benefits in COPD: effects and mechanisms of supramaximal High-Intensity Training)
Reporting period: 2023-07-01 to 2025-12-31
Chronic obstructive pulmonary disease (COPD) is one of the deadliest societal diseases of the 21st century, affecting more than 250 million people with prevalence rates still climbing. Today, the primary focus of COPD treatment is on improving lung function, and less attention is paid to the substantial negative impact of extrapulmonary manifestations, that is changes outside of the lungs. Key extrapulmonary manifestations include decreased or impaired brain, muscle, and cardiac functions. E.g. quadriceps muscle atrophy (loss of muscle mass) is associated with a 4-fold increase in mortality , and people with coexisting COPD and cognitive dysfunction (i.e. reduced cognitive ability) have a rate of death nearly 3-times as high compared to having each condition alone. Extrapulmonary manifestations are also, independent of the degree of lung impairment, closely linked to decreased quality of life, reduced daily physical activity, increased healthcare use, exercise intolerance, and increased symptom. Therefore, the need for new effective treatment modalities that go beyond the lungs are urgently needed. The aim of COPD-HIT is to pave the way for new understanding of the development and treatment of extrapulmonary manifestations in COPD with a focus on brain healthy, muscle quality, and cardiac function.
To do this, the project focus on the following research objectives (RO):
● RO1) Determine the effect of supramaximal High-Intensity Training (HIT) on the brain, muscle, and heart
● RO2) Determine how exercise training and inflammation impacts the trajectories of neurodegeneration
● RO3) Develop a novel in-vitro model to determine signaling pathways following various loading intensities
Through successful completion of RO1-3, the expected outcomes of the COPD-HIT are:
● RO1) a novel, ground-breaking treatment modality that can overcome the barriers associated with traditional moderate-intensity continous exercise, for the first time, enabling multiple extrapulmonary benefits using the same treatment modality.
● RO2) pioneer evidence on the impact of exercise at different intensities to reduce neurodegeneration in COPD and to what extent inflammation mediates neurodegeneration and exercise treatment responses over time.
● RO3) an innovative and valid in-vitro model and novel evidence on signaling pathways to different loading regimens in normoxia and hypoxia – opening new frontiers in COPD exercise research that could be used to design new exercise modalities and identify novel targets for future treatment.
To do this, the project focus on the following research objectives (RO):
● RO1) Determine the effect of supramaximal High-Intensity Training (HIT) on the brain, muscle, and heart
● RO2) Determine how exercise training and inflammation impacts the trajectories of neurodegeneration
● RO3) Develop a novel in-vitro model to determine signaling pathways following various loading intensities
Through successful completion of RO1-3, the expected outcomes of the COPD-HIT are:
● RO1) a novel, ground-breaking treatment modality that can overcome the barriers associated with traditional moderate-intensity continous exercise, for the first time, enabling multiple extrapulmonary benefits using the same treatment modality.
● RO2) pioneer evidence on the impact of exercise at different intensities to reduce neurodegeneration in COPD and to what extent inflammation mediates neurodegeneration and exercise treatment responses over time.
● RO3) an innovative and valid in-vitro model and novel evidence on signaling pathways to different loading regimens in normoxia and hypoxia – opening new frontiers in COPD exercise research that could be used to design new exercise modalities and identify novel targets for future treatment.
Project Duration: 2023/07/01 – 2028/06/30.We are currently at the end of month 25 out of 60 for the COPD-HIIT project—approximately 43% of the total project duration.
RO1 and RO2 are based on an international, multicentre randomized controlled trial that will run throughout the project. Data collection for RO1 is expected to be completed in 2025, while RO2 will continue until the end of 2027. At this moment, the following progress has been achieved.
• RO1: To date, 49 out of 70 individuals with COPD (including an anticipated 15% dropout rate) have been enrolled. The estimated completion of data collection remains on schedule (end of 2025) or may be slightly delayed into early 2026. Encouragingly, the actual dropout rate is only 6%, considerably lower than the projected 15%.
• RO2: So far, 31 out of 46 individuals with COPD have been included in the standard care group. Completion is expected by the end of 2027, or slightly delayed into early 2028. Again, dropout rates are much lower than anticipated—currently at 3% in the standard care group compared to the estimated 30%.
• RO3 will begin in November 2025 with the development and validation of the in vitro model. To validate this model, we first needed a sufficient collection of pre- and post-intervention muscle biopsies from RO1 participants. This milestone has now been achieved.
- Preliminary in vitro findings indicate that short-duration, high-intensity loading (mimicking supramaximal HIT in vivo) leads to greater relative mRNA expression of mitochondrial proteins NDU and ND4 under hypoxia. Conversely, long-duration, low-intensity loading (mimicking in vivo MICT) results in higher expression of NDU and ND4 under normoxia. The former outcome aligns with our hypothesis for RO3, while the latter was unexpected.
Milestones
• Collaboration Agreement signed between Umeå University (Host University) and Hasselt University (Collaborator).
• Data collection initiated on 2023-11-09.
• Study protocol published: Jakobsson J, et al Trials. 2024 Oct 8;25(1):664. doi: 10.1186/s13063-024-08481-3.
• First abstracts submitted to the European Respiratory Society Annual Congress (Amsterdam, September 2025)
Abstract 1: Oral Presentation (Top 5% of abstracts): Multi-domain cognitive function in COPD and matched controls
Abstract 2: Poster Presentation: Associations of cognitive and quadriceps function in persons with COPD
In-vitro data (RO3) Preliminary experiments using the FlexCell System indicate that: Short-duration, high-intensity loading (mimicking supramaximal HIT in vivo) led to greater relative mRNA expression of mitochondrial proteins NDU and ND4 under hypoxia. Long-duration, low-intensity loading (mimicking MICT in vivo) led to higher relative mRNA expression of NDU and ND4 under normoxia. The high-intensity findings align with the RO3 hypothesis, while the low-intensity findings were unexpected.
RO1 and RO2 are based on an international, multicentre randomized controlled trial that will run throughout the project. Data collection for RO1 is expected to be completed in 2025, while RO2 will continue until the end of 2027. At this moment, the following progress has been achieved.
• RO1: To date, 49 out of 70 individuals with COPD (including an anticipated 15% dropout rate) have been enrolled. The estimated completion of data collection remains on schedule (end of 2025) or may be slightly delayed into early 2026. Encouragingly, the actual dropout rate is only 6%, considerably lower than the projected 15%.
• RO2: So far, 31 out of 46 individuals with COPD have been included in the standard care group. Completion is expected by the end of 2027, or slightly delayed into early 2028. Again, dropout rates are much lower than anticipated—currently at 3% in the standard care group compared to the estimated 30%.
• RO3 will begin in November 2025 with the development and validation of the in vitro model. To validate this model, we first needed a sufficient collection of pre- and post-intervention muscle biopsies from RO1 participants. This milestone has now been achieved.
- Preliminary in vitro findings indicate that short-duration, high-intensity loading (mimicking supramaximal HIT in vivo) leads to greater relative mRNA expression of mitochondrial proteins NDU and ND4 under hypoxia. Conversely, long-duration, low-intensity loading (mimicking in vivo MICT) results in higher expression of NDU and ND4 under normoxia. The former outcome aligns with our hypothesis for RO3, while the latter was unexpected.
Milestones
• Collaboration Agreement signed between Umeå University (Host University) and Hasselt University (Collaborator).
• Data collection initiated on 2023-11-09.
• Study protocol published: Jakobsson J, et al Trials. 2024 Oct 8;25(1):664. doi: 10.1186/s13063-024-08481-3.
• First abstracts submitted to the European Respiratory Society Annual Congress (Amsterdam, September 2025)
Abstract 1: Oral Presentation (Top 5% of abstracts): Multi-domain cognitive function in COPD and matched controls
Abstract 2: Poster Presentation: Associations of cognitive and quadriceps function in persons with COPD
In-vitro data (RO3) Preliminary experiments using the FlexCell System indicate that: Short-duration, high-intensity loading (mimicking supramaximal HIT in vivo) led to greater relative mRNA expression of mitochondrial proteins NDU and ND4 under hypoxia. Long-duration, low-intensity loading (mimicking MICT in vivo) led to higher relative mRNA expression of NDU and ND4 under normoxia. The high-intensity findings align with the RO3 hypothesis, while the low-intensity findings were unexpected.
As highlighted in the Milestones above, data collection is progressing according to plan for all research objectives (ROs). Definitive breakthroughs or advances significantly beyond the state-of-the-art will be determined once RO1 is fully completed (end of 2025 / early 2026), when primary analyses can begin. Nonetheless, several early findings already suggest important advances:
1. RO1 & RO2: Baseline findings challenge the current state-of-the-art in COPD and cognitive function:
• Prevailing evidence suggests that aerobic exercise capacity is the key determinant of cognitive function in COPD.
• Our baseline data, however, indicate that anaerobic capacity (measured using the Borg Cycle Strength Test, BCST)—and not aerobic capacity (measured using CPET)—is more strongly associated with multiple cognitive domains.
• This is a novel and potentially paradigm-shifting finding, directly supporting our trial hypothesis of the role of exercise intensity for cognitive benefits in COPD and may open new perspectives for rehabilitation strategies in COPD.
2.RO3 preliminary findings partially unexpected:
• In line with our hypothesis, short-duration, high-intensity loading (supramaximal HIT mimic) under hypoxia produced a larger relative mRNA expression of mitochondrial proteins NDU and ND4.
• Unexpectedly, under normoxia, the long-duration, lower-intensity loading (MICT mimic) resulted in higher expression of the same mitochondrial proteins.
• These findings suggest that cellular responses to exercise intensity may be context-dependent (hypoxia vs. normoxia), offering new mechanistic insights into exercise physiology.
• Follow-up analyses comparing in-vitro and in-vivo biopsy responses (starting late 2025) will clarify whether this unexpected result holds, with potential implications for both COPD and exercise science more broadly.
1. RO1 & RO2: Baseline findings challenge the current state-of-the-art in COPD and cognitive function:
• Prevailing evidence suggests that aerobic exercise capacity is the key determinant of cognitive function in COPD.
• Our baseline data, however, indicate that anaerobic capacity (measured using the Borg Cycle Strength Test, BCST)—and not aerobic capacity (measured using CPET)—is more strongly associated with multiple cognitive domains.
• This is a novel and potentially paradigm-shifting finding, directly supporting our trial hypothesis of the role of exercise intensity for cognitive benefits in COPD and may open new perspectives for rehabilitation strategies in COPD.
2.RO3 preliminary findings partially unexpected:
• In line with our hypothesis, short-duration, high-intensity loading (supramaximal HIT mimic) under hypoxia produced a larger relative mRNA expression of mitochondrial proteins NDU and ND4.
• Unexpectedly, under normoxia, the long-duration, lower-intensity loading (MICT mimic) resulted in higher expression of the same mitochondrial proteins.
• These findings suggest that cellular responses to exercise intensity may be context-dependent (hypoxia vs. normoxia), offering new mechanistic insights into exercise physiology.
• Follow-up analyses comparing in-vitro and in-vivo biopsy responses (starting late 2025) will clarify whether this unexpected result holds, with potential implications for both COPD and exercise science more broadly.