Unraveling the link: locomotor activity exerts a dual role in predicting Achilles tendon healing and boosting regeneration in mice

Melisa Faydaver; Mohammad El Khatib; Valentina Russo; Mara Rigamonti; Marcello Raspa; Oriana Di Giacinto; Paolo Berardinelli; Annunziata Mauro; Ferdinando Scavizzi; Fabrizio Bonaventura; Valentina Mastrorilli; Luca Valbonetti; Barbara Barboni

doi:10.3389/fvets.2023.1281040

Unraveling the link: locomotor activity exerts a dual role in predicting Achilles tendon healing and boosting regeneration in mice

Front Vet Sci. 2023 Dec 21:10:1281040. doi: 10.3389/fvets.2023.1281040. eCollection 2023.

Affiliations

¹ Unit of Basic and Applied Biosciences, Department of Biosciences, Agro-Food and Environmental Technologies, University of Teramo, Teramo, Italy.
² Tecniplast S.p.A., Buguggiate, Italy.
³ National Research Council, Institute of Biochemistry and Cell Biology (CNR-IBBC/EMMA/Infrafrontier/IMPC), International Campus 'A. Buzzati-Traverso', Rome, Italy.
⁴ PLAISANT S.r.l., Rome, Italy.

^# Contributed equally.

Abstract

Introduction: Tendon disorders present significant challenges in the realm of musculoskeletal diseases, affecting locomotor activity and causing pain. Current treatments often fall short of achieving complete functional recovery of the tendon. It is crucial to explore, in preclinical research, the pathways governing the loss of tissue homeostasis and its regeneration. In this context, this study aimed to establish a correlation between the unbiased locomotor activity pattern of CRL:CD1 (ICR) mice exposed to uni- or bilateral Achilles tendon (AT) experimental injuries and the key histomorphometric parameters that influence tissue microarchitecture recovery.

Methods: The study involved the phenotyping of spontaneous and voluntary locomotor activity patterns in male mice using digital ventilated cages (DVC^®) with access to running wheels either granted or blocked. The mice underwent non-intrusive 24/7 long-term activity monitoring for the entire study period. This period included 7 days of pre-injury habituation followed by 28 days post-injury.

Results and discussion: The results revealed significant variations in activity levels based on the type of tendon injury and access to running wheels. Notably, mice with bilateral lesions and unrestricted wheel access exhibited significantly higher activity after surgery. Extracellular matrix (ECM) remodeling, including COL1 deposition and organization, blood vessel remodeling, and metaplasia, as well as cytological tendon parameters, such as cell alignment and angle deviation were enhanced in surgical (bilateral lesion) and husbandry (free access to wheels) groups. Interestingly, correlation matrix analysis uncovered a strong relationship between locomotion and microarchitecture recovery (cell alignment and angle deviation) during tendon healing. Overall, this study highlights the potential of using mice activity metrics obtained from a home-cage monitoring system to predict tendon microarchitecture recovery at both cellular and ECM levels. This provides a scalable experimental setup to address the challenging topic of tendon regeneration using innovative and animal welfare-compliant strategies.

Keywords: Achilles tendon; extracellular matrix; histomorphology; home-cage monitoring; locomotor activity; tendon regeneration.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie Grant Agreement ID 955685—Perspective for Future Innovation in Tendon Repair H2020MSCA-ITN-EJD-P4 FIT and from the European Union—NextGenerationEU—under the Italian Ministry of University and Research (MUR) National Innovation Ecosystem grant no. ECS00000041 – VITALITY – CUP C43C22000380007.