Both aerobic and combined exercise triggered robust inflammatory gene expression responses in CKD skeletal muscle at 24 hours post-exercise, with unexpected downregulation of mitochondrial-related pathways, highlighting mitochondrial dysfunction as a potential barrier to effective exercise adaptation in this population.
Key Findings
Results
Aerobic exercise resulted in substantially more differentially expressed genes than combined exercise in CKD skeletal muscle at 24 hours post-exercise.
Following AE, 1480 genes were upregulated and 1554 genes were downregulated.
CE resulted in 556 upregulated and 115 downregulated genes.
n = 4 per group; biopsies collected at baseline and 24h after the first bout of exercise from vastus lateralis.
Bulk RNA sequencing was used to identify differentially expressed genes.
Results
The most upregulated gene following aerobic exercise was CHI3L1, with the top upregulated genes being associated with inflammation.
CHI3L1 had a log₂FC of 10.7, making it the most upregulated gene after AE.
The second and third most upregulated genes after AE were SAA2 and PTX3.
All three top upregulated genes (CHI3L1, SAA2, PTX3) are associated with inflammation.
These findings were observed at the 24-hour post-exercise timepoint.
Results
The most upregulated gene following combined exercise was SFN, with MT1A also among the most highly upregulated genes.
SFN had a log₂FC of 6.8 after CE, making it the most highly upregulated gene in that condition.
MT1A was also among the most highly upregulated genes after CE.
The magnitude of the top upregulated gene in CE (log₂FC 6.8) was lower than in AE (log₂FC 10.7).
Results
Enrichment analysis revealed strong activation of inflammatory and cellular senescence pathways after exercise, particularly following aerobic exercise.
Pathway enrichment analysis was performed on DEGs identified between baseline and post-exercise samples.
Inflammatory pathways and cellular senescence pathways showed strong activation.
These inflammatory responses were described as potentially 'indicative of early repair processes.'
The inflammatory response was observed in both AE and CE conditions.
The activation of senescence-related pathways was noted particularly after AE.
Results
Mitochondrial function-related pathways were downregulated at 24 hours post-exercise, particularly after aerobic exercise.
Downregulation of mitochondrial function-related processes was identified through enrichment analysis.
This downregulation was described as 'unexpected' by the authors.
The finding was more pronounced after AE compared to CE.
Authors noted it is not possible to determine whether findings reflect impaired mitochondrial adaptation or a recovery-phase return of mitochondrial gene expression to baseline, in the absence of earlier post-exercise timepoints.
Mitochondrial dysfunction was highlighted as 'a potential barrier to effective exercise adaptation and a possible therapeutic target in this population.'
Methods
The study examined skeletal muscle transcriptomic responses in non-dialysis CKD patients randomised to 12 weeks of thrice-weekly aerobic or combined exercise.
Participants had stage 3b-4 CKD and were drawn from the ExTRA CKD trial.
n = 4 per group (AE and CE).
Exercise was performed thrice-weekly for 12 weeks.
Vastus lateralis biopsies were collected at baseline and 24 hours after the first bout of exercise.
Baker L, Graham-Brown M, Wilkinson T, Smith A, Watson E. (2026). Transcriptomic response of skeletal muscle to acute aerobic versus combined exercise in chronic kidney disease.. PloS one. https://doi.org/10.1371/journal.pone.0324303