Comprehensive proteome analysis of human skeletal muscle in cachexia and sarcopenia: a pilot study

Abstract

BackgroundCancer cachexia (cancer‐induced muscle wasting) is found in a subgroup of cancer patients leaving the patients with a poor prognosis for survival due to a lower tolerance of the chemotherapeutic drug. The cause of the muscle wasting in these patients is not fully understood, and no predictive biomarker exists to identify these patients early on. Skeletal muscle loss is an inevitable consequence of advancing age. As cancer frequently occurs in old age, identifying and differentiating the molecular mechanisms mediating muscle wasting in cancer cachexia vs. age‐related sarcopenia are a challenge. However, the ability to distinguish between them is critical for early intervention, and simple measures of body weight may not be sufficiently sensitive to detect cachexia early.MethodsWe used a range of omics approaches: (i) undepleted proteome was quantified using advanced high mass accuracy mass spectrometers in SWATH‐MS acquisition mode; (ii) phospho epitopes were quantified using protein arrays; and (iii) morphology was assessed using fluorescent microscopy.ResultsWe quantified the soluble proteome of muscle biopsies from cancer cachexia patients and compared them with cohorts of cancer patients and healthy individuals with and without age‐related muscle loss (aka age‐related sarcopenia). Comparing the proteomes of these cohorts, we quantified changes in muscle contractile myosins and energy metabolism allowing for a clear identification of cachexia patients. In an in vitro time lapse experiment, we mimicked cancer cachexia and identified signal transduction pathways governing cell fusion to play a pivotal role in preventing muscle regeneration.ConclusionsThe 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.

Muscle wasting and sarcopenia in heart failure: a brief overview of the current literature

“…This is also true for sarcopenia in healthy ageing. 31,32 It has been established that patients with HF and sarcopenia have impaired endothelium function with lower vasodilation having a negative impact of exercise capacity, which is particularly prevalent in sarcopenic patients. On the other hand, decreased exercise capacity and decreased physical activity act hand in hand in aggravating skeletal muscle loss, in itself accelerated by an imbalance in protein senescence and degradation.…”

“…30 The human skeletal muscle proteome project is currently underway to characterize muscle proteins and the way they change during ageing and disease. 31,32 It has been established that patients with HF and sarcopenia have impaired endothelium function with lower vasodilation having a negative impact of exercise capacity, which is particularly prevalent in sarcopenic patients. 33 Anorexia is likewise very prevalent in patients with HF as assessed using a 6-point Likert scale.…”

Silver linings on the horizon: highlights from the 10th Cachexia Conference

“…It did not come as a surprise that they won the poster price for this presentation. Alexander Ebhardt et al . (Systems Biology Ireland) gave an overview of ageing effects in myogenesis.…”

“…It did not come as a surprise that they won the poster price for this presentation. Alexander Ebhardt et al 10 (Systems Biology Ireland) gave an overview of ageing effects in myogenesis. He showed that highly regulated proteins in foetal are dysregulated in ageing 83 years as function of myogenesis.…”

Aging Skeletal Muscle Proteomics Finds Changes in Spliceosome, Immune factors, Proteostasis and Mitochondria

“…However, these studies were limited in size, focused on cancer cachexia, analyzed single fibers, did not account for levels of physical activity or did not explore the effect of aging over its continuous range and, therefore, could not distinguish changes due to aging from those due to disease or sedentary state [14][15][16][17][18] . To overcome these earlier limitations, we have performed a quantitative mass spectrometry-based proteome analysis (tandem mass tag, TMT) of skeletal muscle biopsies obtained from individuals distributed over a wide age range, who were extremely healthy based on strict objective clinical criteria.…”