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Phosphocreatine Rescues Intestinal Epithelial Metabolic Dysfunction Related to Creatine Kinase Loss and Is Protective
Geetha Bhagavatula1, Corey S Worledge2, Ciara Schaepe1
1Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Children's Hospital Colorado, Aurora, Colorado; Division of Gastroenterology and Hepatology, Mucosal Inflammation Program, Department of Medicine, University of Colorado, Aurora, Colorado.
Loss of creatine kinase (CK) impairs intestinal epithelial cell function and energy metabolism in inflammatory bowel disease. Supplementing phosphocreatine (PCr) rescues these defects and improves colitis in mice.
Area of Science:
- Cellular energetics
- Gastroenterology
- Molecular biology
Background:
- Inflammatory bowel disease (IBD) is linked to intestinal energy metabolism defects, specifically reduced creatine kinase (CK) expression.
- CK is vital for cellular energy buffering, managing the balance between ATP and phosphocreatine (PCr).
- The functional impact of CK deficiency on intestinal epithelial cells (IECs) in IBD is not well understood.
Purpose of the Study:
- To investigate the consequences of CK deficiency on IEC energetics and function.
- To identify a potential therapeutic strategy to overcome CK loss in IBD.
Main Methods:
- Creatine kinase-brain isoform knockdown (CKB KD) in T84 cells and knockout (CK dKO) in mouse colonoids.
- Assessed cellular energy metabolism (ATP levels, oxidative phosphorylation) and IEC functions (barrier integrity, proliferation, wound healing).
- Evaluated the efficacy of phosphocreatine (PCr) supplementation in vitro and in a murine colitis model.
Main Results:
- CK deficiency led to reduced ATP levels, impaired oxidative phosphorylation, and diminished IEC proliferation and barrier function.
- Phosphocreatine (PCr) supplementation restored ATP levels, normalized IEC proliferation and barrier integrity.
- Oral PCr administration in mice with colitis ameliorated disease severity and improved histological outcomes.
Conclusions:
- CK loss in IBD contributes to defective energy metabolism and impaired IEC function.
- Phosphocreatine (PCr) supplementation effectively counteracts the detrimental effects of CK loss.
- PCr represents a promising therapeutic approach for managing inflammatory bowel disease.
