The effects of physical prehabilitation: Improved liver regeneration and mitochondrial function after ALPPS operation in a rodent model

Abstract

Background To identify the role of physical prehabilitation (PP) in liver regeneration, mitochondrial function, biogenesis, and inflammatory response was investigated after associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) in a rodent model. Methods Male Wistar rats (n = 60) underwent ALPPS. Animals were divided (n = 30) to the physical prehabilitation group (PP) and sedentary group (S). The animals were exsanguinated before (0 hour) and 24, 48, 72, or 168 hours after the operation. Regeneration rate and proliferation index were assessed. Mitochondrial function, biogenesis, and inflammatory response were evaluated. Results Regeneration rate and Ki67 index were significantly increased in the PP group compared to the S group (P < .001). Due to the changes in oxidative capacity and ATP production rate, the P/O ratio of PP group compared to the S group was significantly increased (P < .05). PP group was characterized by accelerated mitochondrial biogenesis and less intense inflammatory response compared to the S group. Conclusions To our knowledge, this is the first demonstration of the beneficial effects of PP on liver regeneration, mitochondrial function, biogenesis, and the inflammatory response after ALPPS.

The effect of Cyclophilin D depletion on liver regeneration following associating liver partition and portal vein ligation for staged hepatectomy

“…This, along with the robust energy-demanding regeneration led to an energetic imbalance [ 5 ]. Proceeding with our studies on mitochondrial function after ALPPS, we demonstrated that preoperative exercise applied as physical prehabilitation could significantly enhance mitochondrial function and biogenesis along with an even more powerful regeneration [ 6 ].…”

“…Mitochondrial ATP synthesis was investigated as previously described [ 6 ]. Incubation medium was supplemented with NADP+ (1.5 mM), hexokinase (2 U/ml), glucose 6-phosphate dehydrogen- ase (3.84 U/ml), 2.5 mM glucose, and 50 μM P1,P5-di(adenosine-5’) pentaphosphate (inhibitor of adenylate kinase).…”

“…As previously reported [ 5 , 6 ], oxygen consumption was assessed with an Oxygraph-2K® high resolution respirometry system (Oroboros Instruments, Innsbruck, Austria) by measuring reduced nicotinamide adenine dinucleotide dehydrogenase (I complex) and succinate dehydrogenase (II complex). Basal function (state 4) and induced function stimulated by adenosine 5′-diphosphate (ADP) were measured in GM (complex I) and succinate medium (complex II).…”

“…Basal NAD(P)H levels were measured when only mitochondria had been added to the incubation medium. GM or succinate were added for the measurement of induced production [ 5 , 6 ].…”

“…Besides of the rapid increase of the liver volume, there may be a lagging functional recovery following ALPPS [ 4 ]. According to our previous studies [ 5 , 6 ], impaired mitochondrial function and biogenesis could explain the inadequate functional regeneration. Comparing ALPPS to conventional two-stage hepatectomy, we found that while mitochondrial function and mitochondrial biogenesis pathway coordinator peroxisome proliferator-activated receptor γ co-activator 1-α (PGC1-α) along with its transcription factor Nuclear Respiratory Factor (NRF) 1 were preserved after conventional two-stage hepatectomy, they decreased and remained impaired after ALPPS.…”