1. Academic Validation
  2. Loss of adenosine A3 receptors accelerates skeletal muscle regeneration in mice following cardiotoxin-induced injury

Loss of adenosine A3 receptors accelerates skeletal muscle regeneration in mice following cardiotoxin-induced injury

  • Cell Death Dis. 2023 Oct 28;14(10):706. doi: 10.1038/s41419-023-06228-7.
Nastaran Tarban # 1 Albert Bálint Papp # 2 Dávid Deák 3 Péter Szentesi 4 Hajnalka Halász 1 Andreas Patsalos 5 László Csernoch 4 Zsolt Sarang 6 Zsuzsa Szondy 7 8
Affiliations

Affiliations

  • 1 Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, Debrecen, Hungary.
  • 2 Doctoral School of Dental Sciences, University of Debrecen, Debrecen, Hungary.
  • 3 Laboratory Animal Facility, Life Science Building, University of Debrecen, Debrecen, Hungary.
  • 4 Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
  • 5 Departments of Medicine and Biological Chemistry, Johns Hopkins University School of Medicine, Institute for Fundamental Biomedical Research, Johns Hopkins All Children's Hospital, St, Petersburg, FL, USA.
  • 6 Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
  • 7 Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary. szondy@med.unideb.hu.
  • 8 Division of Dental Biochemistry, Department of Basic Medical Sciences, Faculty of Dentistry, University of Debrecen, Debrecen, Hungary. szondy@med.unideb.hu.
  • # Contributed equally.
Abstract

Skeletal muscle regeneration is a complex process orchestrated by multiple interacting steps. An increasing number of reports indicate that inflammatory responses play a central role in linking initial muscle injury responses to timely muscle regeneration following injury. The nucleoside adenosine has been known for a long time as an endogenously produced anti-inflammatory molecule that is generated in high amounts during tissue injury. It mediates its physiological effects via four types of adenosine receptors. From these, adenosine A3 receptors (A3Rs) are not expressed by the skeletal muscle but are present on the surface of various inflammatory cells. In the present paper, the effect of the loss of A3Rs was investigated on the regeneration of the tibialis anterior (TA) muscle in mice following cardiotoxin-induced injury. Here we report that regeneration of the skeletal muscle from A3R-/- mice is characterized by a stronger initial inflammatory response resulting in a larger number of transmigrating inflammatory cells to the injury site, faster clearance of cell debris, enhanced proliferation and faster differentiation of the satellite cells (the muscle stem cells), and increased fusion of the generated myoblasts. This leads to accelerated skeletal muscle tissue repair and the formation of larger myofibers. Though the infiltrating immune cells expressed A3Rs and showed an increased inflammatory profile in the injured A3R-/- muscles, bone marrow transplantation experiments revealed that the increased response of the tissue-resident cells to tissue injury is responsible for the observed phenomenon. Altogether our data indicate that A3Rs are negative regulators of injury-related regenerative inflammation and consequently also that of the muscle fiber growth in the TA muscle. Thus, inhibiting A3Rs might have a therapeutic value during skeletal muscle regeneration following injury.

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