CPEB1 directs muscle stem cell activation by reprogramming the translational landscape

While all cells in the human body have the same basic components, the body relies on hundreds of specialised cell types to ensure the proper functioning of tissues, organs, and systems. So, what happens when one of these specialised cells is damaged? Reserve cells, know as stem cells, enter the cell cycle and begin the processes of becoming the specialised cell they need to replace. This process is guided by external signals and involves a variety of changes within the cell itself. Understanding what causes a stem cell to enter the cell cycle, and what happens when it does, is key to determining how we can maximise the therapeutic potential of these “blank slate” cells to repair injured tissues or treat diseases that involve the loss or destruction of specific cell types like neurons or white blood cells. In this paper by Zeng and colleagues, researchers use LC-MS/MS to study the activation of a particular type of stem cell, Satellite cells (SC), that have the potential to repair damaged skeletal muscle. Importantly, the study used an in situ fixation technique to obtain truly inactive, or quiescent, SC and then compared them in a pair-wise manner to different cell populations, including SC in early stages of activation, activated SC, and proliferating SC in culture. This allowed them to capture a timeline of proteomic changes during differentiation.  Further, the proteomics data was compared to previously acquired RNA-seq data, which highlighted a set of proteins that were highly unregulated despite low levels of RNA expression, and another set that had low abundance when their transcript levels were high, suggested that some mechanisms of SC activation were occurring at the translational level. The proteomic vs. transcriptomic findings were used to guide a set of targeted experiments that examined the role of a specific protein, Cytoplasmic Polyadenylation Element Binding protein 1 (CPEB1) in post-transcriptional control of protein translation and SC activation. Identification and characterisation of these key regulators is an integral step forward in the therapeutic use of stems cells, including SC, in tissue repair.

How was PEAKS used?

Data was acquired using a timsTOF Pro mass spectrometer from Bruker Daltonics. Protein identification and quantification was completed using PEAKS Studio X+, which is vendor neutral and supports ion mobility spectrometry data. The authors used spectral counting for the label-free quantification, as well as the normalised spectral abundance factor (NSAF) method (Zhu et al., 2010). Data exported from PEAKS was examined using a Student’s t-test and hierarchical clustering analysis.

Zeng W, Yue L, Lam KSW, Zhang W, So WK, Tse EHY, Cheung TH. CPEB1 directs muscle stem cell activation by reprogramming the translational landscape. Nat Commun. 2022 Feb 17;13(1):947. doi:10.1038/s41467-022-28612-1. PMID: 35177647.


Skeletal muscle stem cells, also called Satellite Cells (SCs), are actively maintained in quiescence but can activate quickly upon extrinsic stimuli. However, the mechanisms of how quiescent SCs (QSCs) activate swiftly remain elusive. Here, using a whole mouse perfusion fixation approach to obtain bona fide QSCs, we identify massive proteomic changes during the quiescence-to-activation transition in pathways such as chromatin maintenance, metabolism, transcription, and translation. Discordant correlation of transcriptomic and proteomic changes reveals potential translational regulation upon SC activation. Importantly, we show Cytoplasmic Polyadenylation Element Binding protein 1 (CPEB1), post-transcriptionally affects protein translation during SC activation by binding to the 3′ UTRs of different transcripts. We demonstrate phosphorylation-dependent CPEB1 promoted Myod1 protein synthesis by binding to the cytoplasmic polyadenylation elements (CPEs) within its 3′ UTRs to regulate SC activation and muscle regeneration. Our study characterizes CPEB1 as a key regulator to reprogram the translational landscape directing SC activation and subsequent proliferation.