Comprehensive proteome analysis of skeletal muscle in cachexia and age-related sarcopenia: a pilot comparison of in vivo and in vitro models

As cancer frequently occurs in old age, identifying and differentiating molecular mechanisms mediating muscle wasting in cancer cachexia versus age-related sarcopenia is challenging. We aimed to characterize the underlying mechanism leading to proteome changes in cachectic skeletal muscle. We compared the proteome of muscle from healthy elderly people with and without age-related sarcopenia, with that of muscle obtained from diagnosed weight-stable cancer and cancer cachectic patients. Using multiple proteomic quantification approaches, we identified a protein signature that is able to identify cancer cachexia patients and differentiate them from the other comparison groups. Main components of the protein signature were validated in a separate cohort of patients. To relate observed proteome changes in cancer cachexia patients back to underlying molecular mechanisms, we mimicked environmental challenges of muscle regeneration using an in vitro system of myogenesis. We investigated changes in the proteome and signal transduction in the presence or absence of TNFα as a function of time. We identified aberrations in key proteins of energy metabolism and signaling pathways upon exposure to TNFα which reflect observed changes in human muscle biopsies. The work presented here lays the foundation for further understanding of muscle wasting diseases and holds the promise of overcoming ambiguous weight loss as a measure for defining cachexia to be replaced by a precise protein signature.