Mitochondria Isolated From Bone Mesenchymal Stem Cells Restrain Muscle Disuse Atrophy and Fatty Infiltration After Rotator Cuff Tears

Abstract

Background: Rotator cuff tears (RCTs) commonly lead to muscle atrophy, fibrosis, and fatty infiltration, complicating treatment. Purpose: To investigate the use of mitochondria isolated from bone mesenchymal stem cells (BMSC-Mito) for mitigating complications after RCT, focusing on muscle protection. Study Design: Controlled laboratory study. Methods: RCTs were induced by transecting the tendons of the supraspinatus and infraspinatus in Sprague-Dawley rats. In vivo, 90 rats were randomized into 3 groups: sham (no intervention), RCTs treated with BMSC-Mito, and RCTs treated with phosphate-buffered saline. After 6 weeks of intramuscular injections of BMSC-Mito or phosphate-buffered saline, supraspinatus muscles were harvested for analysis. Evaluations included wet muscle weight, muscle fiber cross-sectional area, fibrosis, fatty infiltration, slow-fast myofiber types and muscle biomechanics, capillary density, mitochondria respiratory chain complex activity, adenosine triphosphate (ATP) concentration, oxidative stress, and mitochondrial ultrastructure. In vitro experiments utilized primary rat skeletal muscle cells pretreated with rhodamine 6G to induce mitochondrial dysfunction, assessing the effects of BMSC-Mito on cell viability, mitochondrial membrane potential, and oxidative stress levels. Results: BMSC-Mito can be effectively transplanted into muscles and integrated into the local mitochondrial network. After RCT, the supraspinatus showed significant mass loss, reduced fiber cross-sectional area, fatty infiltration, and a shift from slow to fast myofiber types, which negatively affected muscle biomechanics. These changes were reversed by BMSC-Mito. BMSC-Mito also preserved vascularity (CD31 and α-SMA) impaired by RCT. Additionally, BMSC-Mito notably improved disuse-induced mitochondrial changes, leading to increased mitochondrial number and COX IV expression; furthermore, BMSC-Mito protected mitochondria morphology and enhanced cytosolic superoxide dismutase activity. This treatment also improved mitochondria respiratory chain complex activity and ATP concentration, reducing oxidative stress. In vitro, BMSC-Mito treatment effectively maintained the mitochondrial membrane potential of skeletal muscle cells, improved cell viability, and restored its mitochondrial function and ATP levels. Conclusion: These findings suggest that BMSC-Mito might play a role in preventing muscle atrophy and fatty infiltration after RCT through the protection of mitochondrial function and the promotion of angiogenesis. Clinical Relevance: BMSC-Mito present a promising therapeutic approach for addressing rotator cuff muscle degeneration.