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ALDH1A1 and ALDH1A3 paralogues of aldehyde dehydrogenase 1 control myogenic differentiation of skeletal muscle satellite cells by retinoic acid-dependent and -independent mechanisms

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Abstract

ALDH1A1 and ALDH1A3 paralogues of aldehyde dehydrogenase 1 (ALDH1) control myogenic differentiation of skeletal muscle satellite cells (SC) by formation of retinoic acid (RA) and subsequent cell cycle adjustments. The respective relevance of each paralogue for myogenic differentiation and the mechanistic interaction of each paralogue within RA-dependent and RA-independent pathways remain elusive.

We analysed the impact of ALDH1A1 and ALDH1A3 activity on myogenesis of murine C2C12 myoblasts. Both paralogues are pivotal factors in myogenic differentiation, since CRISPR/Cas9-edited single paralogue knock-out impaired serum withdrawal-induced myogenic differentiation, while successive recombinant re-expression of ALDH1A1 or ALDH1A3, respectively, in the corresponding ALDH1 paralogue single knock-out cell lines, recovered the differentiation potential. Loss of differentiation in single knock-out cell lines was restored by treatment with RA-analogue TTNPB, while RA-receptor antagonization by AGN 193109 inhibited differentiation of wildtype cell lines, supporting the idea that RA-dependent pathway is pivotal for myogenic differentiation which is accomplished by both paralogues.

However, overexpression of ALDH1-paralogues or disulfiram-mediated inhibition of ALDH1 enzymatic activity not only increased ALDH1A1 and ALDH1A3 protein levels but also induced subsequent differentiation of C2C12 myoblasts independently from serum withdrawal, indicating that ALDH1-dependent myogenic differentiation relies on different cellular conditions. Remarkably, ALDH1-paralogue knock-out impaired the autophagic flux, namely autophagosome cargo protein p62 formation and LC3B-I to LC3B-II conversion, demonstrating that ALDH1-paralogues interact with autophagy in myogenesis. Together, ALDH1 paralogues play a crucial role in myogenesis by orchestration of complex RA-dependent and RA-independent pathways.

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Abbreviations

AGN:

AGN 193109, retinoic acid receptor antagonist

ALDH:

Aldehyde dehydrogenase

Ctrl:

Control

Diff:

Differentiation

DSF:

Disulfiram

FACS:

Fluorescence-activated cell sorting

GFP:

Green fluorescent protein

KO:

Knock-out

LC3B:

Microtubule-associated protein 1 light chain 3 beta

MHC:

Myosin heavy chain

MyoG:

Myogenin

Neo:

Neomycin

P62/SQSTM-1:

Sequestosome-1, ubiquitin-binding protein p62

RA:

Retinoic acid

RAR:

Retinoic acid receptor

RIPA:

Radio-immunoprecipitation assay

SC:

Satellite cell

TTNPB:

Retinoic acid analogue

1A1:

Aldehyde dehydrogenase 1A1

1A3:

Aldehyde dehydrogenase 1A3

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Acknowledgements

We would like to thank E. Beck, S. Baur, Ch. Schustetter, and T. Matt for their excellent technical assistance. We also would like to thank Kerstin Stemmer for the helpful discussion.

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Authors and Affiliations

  1. Anatomy and Cell Biology, Institute of Theoretical Medicine, Faculty of Medicine, University of Augsburg, Augsburg, Germany

    Laura Steingruber, Florian Krabichler & Marco Koch

  2. Department of Neuropathology, Institute of Pathology, Technical University Munich, Munich, Germany

    Laura Steingruber, Florian Krabichler, Sophie Franzmeier, Wei Wu & Jürgen Schlegel

  3. Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, Stanford, CA, USA

    Wei Wu

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Contributions

LS and FK equally performed cell cultivation, experimental implementation, data collection, and analysis, with support from SF, WW, JS, and MK. The first draft of the manuscript was written by LS. All authors commented on previous versions of the manuscript, contributed to the study conception and design, and read and approved the final manuscript.

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Correspondence to Laura Steingruber or Florian Krabichler.

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The manuscript was already submitted as a preprint (Research Square) with the corresponding author’s former last name Rihani. This updated version contains additional results and involves further theories.

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Steingruber, L., Krabichler, F., Franzmeier, S. et al. ALDH1A1 and ALDH1A3 paralogues of aldehyde dehydrogenase 1 control myogenic differentiation of skeletal muscle satellite cells by retinoic acid-dependent and -independent mechanisms. Cell Tissue Res 394, 515–528 (2023). https://doi.org/10.1007/s00441-023-03838-7

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