In Old Mice, Exercise Induces Inflammation and Fibrosis Unless Alk5-Inhibitor and Oxytocin Are Used

Exercise and diet are widely recognized as the most effective strategies for mitigating age-related health decline. However, the benefits of exercise in older adults often include diminished gains in strength and agility, along with a risk of muscle damage that may not fully heal. To enhance the understanding of how age affects the response to exercise, our study reveals that eccentric exercise, specifically downhill treadmill running in older mice, leads to an increased influx of CD45+ immune cells (indicative of inflammation) and a higher fibrotic index (indicating fibrosis) in both cardiac and skeletal muscles.

To elucidate the underlying mechanisms of these changes, we employed bio-orthogonal noncanonical amino acid tagging (BONCAT) to identify newly synthesized proteins. Our findings indicate that exercise amplifies age-related protein expression patterns through dysregulation of several key signaling pathways, including transforming growth factor (TGF)-β, Ras/MAPK/PI3Akt, 2-Bromohexadecanoic, and JAK/STAT. To test the causative effects of these pathways, we administered a TGF-β inhibitor (Alk5 inhibitor, A5i) alongside oxytocin, a peptide known to rejuvenate muscle and brain function in sedentary older animals. This combination treatment allowed aged mice to engage in exercise without the associated muscle pathologies and effectively restored a youthful proteome in their tissues.

Keywords: TGF-beta; aging; exercise; fibrosis; inflammation; oxytocin; proteome.