Abstract
Cachexia presents with ongoing muscle wasting, altering quality of life in cancer patients. Cachexia is a limiting prognostic factor for patient survival and health care costs. Although animal models and human trials have shown mechanisms of motorprotein proteolysis, not much is known about intrinsic changes of muscle functionality in cancer patients suffering from muscle cachexia, and deeper insights into cachexia pathology in humans are needed. To address this question, rectus abdominis muscle samples were collected from several surgical control, non-cachectic and cachectic cancer patients and processed for skinned fibre biomechanics, molecular in vitro motility assays, myosin isoform protein compositions and quantitative ubiquitin polymer protein analysis. In pre-cachectic and cachectic cancer patient samples, maximum force was significantly compromised compared with controls, but showed an unexpected increase in myofibrillar Ca2+ sensitivity consistent with a shift from slow to fast myosin isoform expression seen in SDS-PAGE analysis and in vitro motility assays. Force deficit was specific for ‘cancer’, but not linked to presence of cachexia. Interestingly, quantitative ubiquitin immunoassays revealed no major changes in static ubiquitin polymer protein profiles, whether cachexia was present or not and were shown to mirror profiles in control patients. Our study on muscle function in cachectic patients shows that abdominal wall skeletal muscle in cancer cachexia shows signs of weakness that can be partially attributed to intrinsic changes to contractile motorprotein function. On protein levels, static ubiquitin polymeric distributions were unaltered, pointing towards evenly up-regulated ubiquitin protein turnover with respect to ubiquitin conjugation, proteasome degradation and de-ubiquitination.
Highlights
Cancer cachexia is a severe multi-factorial syndrome associated with loss of lean body mass and adipose tissue
Ca2+ sensitivity of the contractile apparatus is increased in rectus abdominis muscle from cachectic cancer patients
Determinants of muscle performance were previously described in cancer patients [34,35,36], few studies focus on cachexia as a main determinant
Summary
Cancer cachexia is a severe multi-factorial syndrome associated with loss of lean body mass and adipose tissue. Active hypercatabolism vastly outweighs consequences of starvation, malnutrition or immobility [1]. The mechanisms underlying weight loss are highly complex and sustained by chronic inflammation and pro-inflammatory cytokines [2, 3]. Loss of body weight can be as high as ~25% in the final months of the patient. In pancreatic cancer, ~85% of patients become cachectic [1]. Most authors define ‘cachexia’ solely by weight loss a 2013 The Authors
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