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Individuals with chronic liver disease experience progressive muscle wasting, weakness, fatigue, and decreased quality of life. Liver transplantation is the only treatment for end-stage liver disease with cirrhosis; however, muscle wasting, strength impairments, activity limitations, and health related quality of life do not return to the level of healthy adults. Currently there is no plan of care for rehabilitation of individuals post-liver transplantation. These individuals are only instructed to gradually increase walking and activity. Walking may increase lower extremity muscle strength; however, walking at a self-selected pace is less effective than resistance exercise. The purpose of this dissertation was to compare the benefits of a home exercise program of targeted lower extremity resistance exercise with benefits of progressive walking in individuals who have undergone liver transplantation. In Chapter 2 we performed a study to validate the ability of several outcome measures to detect changes in strength and activity performance in the population with liver disease and post-liver transplantation. The strength impairment measures of Grip Strength, Heel Rising, and Bridging along with activity limitation measures 30 Second Chair Stand and Six Minute Walk Test (6MWT) were able to differentiate strength and activity performance across levels of liver disease severity including post liver transplantation. Liver disease severity was moderately correlated with the strength impairment measures Bridging and Heel Rising but was not correlated with Grip strength. Liver disease severity was moderately correlated with 6MWT and 30-Second Chair-Stand but was not correlated with the SF-36 physical function scale. Strength impairment measures were strongly correlated with the activity limitation measures. Heel Rising and Bridging were strongly correlated with 30-Second Chair-Standing and 6MWT. Grip strength was moderately correlated with 30-Second Chair-Standing. In Chapter 3 we conducted a randomized controlled trial to assess the benefits of resistance exercise to progressive walking as a treatment plan for improving strength and activity performance in individuals post liver transplantation. We also examined the relationships of the change in muscle strength to the change in activity performance. Both the exercise and walking groups improved in strength and activity performance; however, the group performing the resistance exercise improved more. Bridging, 30 Second Chair Standing, Heel Rising, and 6MWT increased more for the exercise group than the walking group. Additionally, changes in strength were related to the changes in activity performance and health related quality of life. Bridging was correlated with Heel Rising, 30 Second Chair Standing, 6MWT, and the Chronic Liver Disease Questionnaire. In Chapter 4 we discuss the clinical relevance of the results of the studies described in the above chapters. We conclude Bridging, Heel Rising, 30 Second Chair Standing, and 6MWT are valid outcome measures to measure changes in strength and activity performance in the population with liver disease. Individuals post liver transplantation improve in strength and activity performance through progressive walking; however, the addition of resistance exercise to the current treatment plan is necessary for greater improvement. Additionally it is clinically relevant that this population was adherent to a home exercise program. Subjects adherent to the exercise program increased in strength and activity performance greater than subjects who were non-adherent.

Indianapolis / By the traditional definition of unintended weight loss, cachexia develops in ~80% of patients with pancreatic ductal adenocarcinoma (PDAC). Here we measure the longitudinal body composition changes in patients with advanced PDAC undergoing FOLFIRINOX therapy. We performed a retrospective review of 53 patients with advanced PDAC on FOLFIRINOX as first line therapy at Indiana University Hospital from July 2010 to August 2015. Demographic, clinical, and survival data were collected. Body composition measurement, trend, univariate and multivariate analysis were performed. Three cachexia phenotypes were identified. The majority of patients, 64%, had Muscle-and-Fat Wasting (MFW), while 17% had Fat-Only Wasting (FW) and 19% had No Wasting (NW). NW had significantly improved overall median survival (OMS) of 22.6 months vs. 13.0 months for FW and 12.2 months for MFW (p=0.02). FW (HR=5.2; 95%CI=1.5-17.3) and MFW (HR=1.8; 95%CI=1.1-2.9) were associated with an increased risk of mortality compared to NW. OMS and risk of mortality did not differ between FW and MFW. Progression of disease, sarcopenic obesity at diagnosis, and primary tail tumors were also associated with decreased OMS. On multivariate analysis cachexia phenotype and chemotherapy response were independently associated with survival. Three phenotypes of cachexia were observed. Moreover, three phenotypes suggests molecular or genetic heterogeneity of host or tumor. Identifying these differences will be vital to defining optimal treatment for cachexia. Survival among FW was as poor as MFW suggesting adipose tissue plays a crucial role in cachexia. Blunting or possibly preventing cachexia may confer a significant survival advantage in patients with advanced PDAC.

Cancer cachexia is a wasting syndrome causing involuntary weight loss and muscle atrophy. PARP1 is a nicotinamide dinucleotide-dependent enzyme that modifies target proteins by PARylation. The reversal process, dePARylation, is mediated by the PARG enzyme. PARP1 inhibitors are potent cancer agents, while PARG inhibitors are in clinical trials for similar cancers. Here we examine the role of PARylation on muscle homeostasis in cancer cachexia. We employed mouse models with inducible muscle specific knockouts of Parp1 (Parp1-IMKO) or Parg (Parg-IMKO) to investigate their implications on skeletal muscle in a cancer cachexia model. We assessed muscle loss, grip strength, and gene expression. Results show that Parp1- IMKO mice had increased muscle wasting, while Parg-IMKO had degradation rates similar to wild-type mice during cancer cachexia. This suggests reduced PARylation might worsen cancer cachexia, while an increase does not. This supports PARG inhibitor development as anticancer alternatives. Our study highlights challenges with PARP1 inhibitors and the need to study PARylation and dePARylation in muscle health during cancer cachexia, impacting clinical strategies using PARP1 or PARG inhibitors.

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