Skeletal Muscle Adaptations Across the Surgical Timeline : Evidence for Prehabilitation to Mitigate Mitochondrial Dysfunction and Inflammation in Hepatopancreatobilairy and Colorectal Cancer Surgery Patients

Hayden, Jack and Gaffney, Christopher and Hendrickse, Paul (2025) Skeletal Muscle Adaptations Across the Surgical Timeline : Evidence for Prehabilitation to Mitigate Mitochondrial Dysfunction and Inflammation in Hepatopancreatobilairy and Colorectal Cancer Surgery Patients. Masters thesis, Lancaster University.

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Abstract

Background Prehabilitation programs aim to improve surgical outcomes and prevent comorbidities, however, the underlying mechanisms remain poorly established. It is established that surgery induces significant physiological stress on the body, therefore this study presents novel findings investigating skeletal muscle molecular adaptations across a surgical timeline whilst investigating the potential benefits of a prehabilitation programme in patients undergoing elective Hepatopancreatobilairy and Colorectal cancer surgery. Methods Twenty-eight patients (17 standard, 11 prehabilitation) provided three muscle biopsies from the vastus lateralis at key timepoints: baseline, presurgery and post-surgery. Patients in the prehabilitation group received HIIT training for a duration of two to four weeks prior to surgery and the comparator group received standard care. Western blotting analysis was completed to investigate changes in anabolic signalling, inflammation markers, and mitochondrial markers. An exploratory analysis on 13 inflammation cytokines was also completed using a LEGENDplex Multiplex bead-based assay. Results Western blotting revealed in the standard care group there was significant surgery-induced degradation of the mitochondrial electron transport complexes (p<0.05) that was not present in the prehabilitation group. IL-6 was significantly lower post-surgery in both cohorts (standard care: p=0.004, prehabilitation: p=0.027) reflecting the removal of a source of inflammation through tumour resection. FoxO3a was also significantly higher in the prehabilitation group following surgery indicating enhanced stress response signalling (p=0.03). An exploratory analysis using the multiplex assay highlighted significant differences for multiple cytokines in both care groups. 3 Conclusion This study presents novel findings regarding surgeries impact of mitochondrial disfunction in skeletal muscle. The findings suggest prehabilitation may protect against surgery-induced skeletal muscle decline through preserving mitochondrial function. This study provides molecular insights into the potential benefits of prehabilitation on a cancer cohort and provides a platform for larger clinical studies to build on these preliminary molecular findings.