Muscle Precursor Cells Enhance Functional Muscle Recovery and Show Synergistic Effects With Postinjury Treadmill Exercise in a Muscle Injury Model in Rats

• Published in: The American journal of sports medicine 2021-03, Vol.49 (4), p.1073-1085
• Main Authors: Contreras-Muñoz, Paola, Torrella, Joan Ramón, Venegas, Vanessa, Serres, Xavier, Vidal, Laura, Vila, Ingrid, Lahtinen, Ilmari, Viscor, Ginés, Martínez-Ibáñez, Vicente, Peiró, José Luis, Järvinen, Tero A.H., Rodas, Gil, Marotta, Mario
• Format: Article
• Language: English
• Subjects: Animals; Injuries; Muscle recovery; Muscle, Skeletal; Muscular Diseases; Musculoskeletal system; Rats; Recovery (Medical); Recovery of Function; Regeneration; Rehabilitation; Sports Medicine; Ultrasonic imaging
• ISSN: 0363-5465; 1552-3365
• DOI: 10.1177/0363546521989235

Background: Skeletal muscle injuries represent a major concern in sports medicine. Cell therapy has emerged as a promising therapeutic strategy for muscle injuries, although the preclinical data are still inconclusive and the potential clinical use of cell therapy has not yet been established. Purpose: To evaluate the effects of muscle precursor cells (MPCs) on muscle healing in a small animal model. Study Design: Controlled laboratory study. Methods: A total of 27 rats were used in the study. MPCs were isolated from rat (n = 3) medial gastrocnemius muscles and expanded in primary culture. Skeletal muscle injury was induced in 24 rats, and the animals were assigned to 3 groups. At 36 hours after injury, animals received treatment based on a single ultrasound-guided MPC (105 cells) injection (Cells group) or MPC injection in combination with 2 weeks of daily exercise training (Cells+Exercise group). Animals receiving intramuscular vehicle injection were used as controls (Vehicle group). Muscle force was determined 2 weeks after muscle injury, and muscles were collected for histological and immunofluorescence evaluation. Results: Red fluorescence–labeled MPCs were successfully transplanted in the site of the injury by ultrasound-guided injection and were localized in the injured area after 2 weeks. Transplanted MPCs participated in the formation of regenerating muscle fibers as corroborated by the co-localization of red fluorescence with developmental myosin heavy chain (dMHC)–positive myofibers by immunofluorescence analysis. A strong beneficial effect on muscle force recovery was detected in the Cells and Cells+Exercise groups (102.6% ± 4.0% and 101.5% ± 8.5% of maximum tetanus force of the injured vs healthy contralateral muscle, respectively) compared with the Vehicle group (78.2% ± 5.1%). Both Cells and Cells+Exercise treatments stimulated the growth of newly formed regenerating muscles fibers, as determined by the increase in myofiber cross-sectional area (612.3 ± 21.4 µm2 and 686.0 ± 11.6 µm2, respectively) compared with the Vehicle group (247.5 ± 10.7 µm2), which was accompanied by a significant reduction of intramuscular fibrosis in Cells and Cells+Exercise treated animals (24.2% ± 1.3% and 26.0% ± 1.9% of collagen type I deposition, respectively) with respect to control animals (40.9% ± 4.1% in the Vehicle group). MPC treatment induced a robust acceleration of the muscle healing process as demonstrated by the decreased number of dMHC-positive regen