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A multi-tissue longitudinal proteomics study to evaluate the suitability of post-mortem samples for pathophysiological research

ABSTRACT: Recent developments in liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS)-based proteomics have drastically increased analytical depth and sample throughput, establishing a robust tool for comprehensive system-wide analyses. Such analyses are instrumental in studying the pathophysiology of diseases. One crucial source of material for this is post-mortem individuals. However, there is a significant gap in our understanding of the multi-organ temporal impacts of body decomposition on the proteome. This deficiency compromises result validity due to challenges in controlling the post-mortem interval (PMI). To address this, we reanalyzed published data to compare the effect of the PMI on the proteome alterations to the disease effects. Additionally, we conducted a clinically relevant time-course experiment using isogenic mice and applied LC-MS/MS in data-independent acquisition (DIA) mode to systematically study the proteome alterations post-mortem. Our experiment uncovered dramatic organ-specific protein regulation post-mortem, with only certain aspects attributable to protein autolysis suggesting active post-mortem protein regulation. Notably, the liver and spleen exhibited substantial proteome changes within hours of PMI, while the heart showed comparatively modest changes even after 96 hours. Subcellular fractionation of the heart led to an unexpected surge in the number of proteins exhibiting abundance differences early in PMI. We conducted a compressive analysis of semi-tryptic peptides for the first time, revealing distinct consensus motifs for different organs, indicating organ-specific protease activity. In conclusion, when designing LC-MS/MS-based studies, meticulous consideration of sample collection is crucial as PMI effects may outweigh disease effects. It is preferred that both experimental and control samples are taken in the operation room, especially for studies including subcellular fractionation or trans-organ comparison. In single-organ studies, the planning should involve careful control of the PMI, preferably by sample matching.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart, Liver, Kidney

SUBMITTER: Christian Beusch

LAB HEAD: Sergey Rodin

PROVIDER: PXD053048 | Pride | 2024-12-17

REPOSITORIES: pride

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Project description:The combined use of multiple omics methods to answer complex system biology questions is growing in biological and medical sciences, as the importance of studying interrelated biological processes in their entirety is increasingly recognized. We applied a combination of metabolomics, lipidomics and proteomics to human bone to investigate the potential of this multi-omics approach to estimate the time elapsed since death (i.e., the post-mortem interval, PMI). This “ForensOMICS” approach has the potential to improve accuracy and precision of PMI estimation of skeletonized human remains, thereby helping forensic investigators to establish the timeline of events surrounding death. Anterior midshaft tibial bone was collected from four female body donors in a fresh stage of decomposition before placement of the bodies to decompose outdoors at the human taphonomy facility managed by the Forensic Anthropological Center at Texas State (FACTS). Bone samples were again collected at selected PMIs (219, 790, 834 and 872 days). Liquid chromatography mass spectrometry (LC-MS) was used to obtain untargeted metabolomic, lipidomic and proteomic profiles from the pre- and post-placement bone samples. Multivariate analysis was used to investigate the three omics blocks by means of Data Integration Analysis for Biomarker discovery using Latent variable approaches for Omics studies (DIABLO), to identify the reduced number of markers that could effectively describe post-mortem changes and classify the individuals based on their PMI. The resulting model showed that pre-placement bone metabolome, lipidome and proteome profiles were clearly distinguishable from post-placement profiles. Metabolites associated with the pre-placement samples, suggested an extinction of the energetic metabolism and a switch towards another source of fuelling (e.g., structural proteins). We were able to identify certain biomolecules from the three groups that show excellent potential for estimation of the PMI, predominantly the biomolecules from the metabolomics block. Our findings suggest that, by targeting a combination of compounds with different post-mortem stability, in future studies we could be able to estimate both short PMIs, by using metabolites and lipids, and longer PMIs, by including more stable proteins.

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A multi-tissue longitudinal proteomics study to evaluate the suitability of post-mortem samples for pathophysiological research

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