Blood Flow Restriction Therapy Stimulates Intercellular Mitochondria Transfer and Improves Muscle Regeneration and Shoulder Function in a Murine Rotator Cuff Injury Model.

Abstract

BACKGROUND: Rotator cuff (RC) tears are among the most common causes of shoulder dysfunction in sports medicine. Muscle atrophy and degeneration are important risk factors for RC tendon retearing and suboptimal recovery of shoulder function after tendon repair. Although blood flow restriction (BFR) can stimulate muscle regeneration after lower extremity trauma and anterior cruciate ligament reconstruction, the mechanisms that underlie BFR remain unknown, and its application to RC tears has not yet been explored. HYPOTHESIS: The authors hypothesized that BFR induces transfer of mitochondria from intramuscular fibro-adipogenic progenitors (FAPs) to myocytes, enhances muscle regeneration, and improves shoulder function after RC injury. STUDY DESIGN: Controlled laboratory study. METHODS: To assess mitochondrial transfer after BFR, the authors used Prrx1-Cre/MitoTag reporter mice, in which FAP mitochondria are labeled. Mice underwent unilateral forelimb BFR, and supraspinatus (SS) muscles were collected at baseline and days 1, 2, 3, 5, and 7 for histology. To model massive RC tears, mice received unilateral SS and infraspinatus tendon transection with denervation (TT+DN) and then were randomized to a BFR (every 3 days) or control group. At 2 or 6 weeks after surgery, SS muscles were analyzed for mitochondrial transfer, fiber size, and fiber-type distribution. Additionally, forelimb gait and weightbearing were captured using the Blackbox system. RESULTS: BFR was associated with increased FAP-mediated mitochondrial transfer in healthy SS muscle as early as 1 day after BFR treatment and lasted for up to 3 days after BFR. The authors observed an enhanced effect of BFR-induced FAP mitochondrial transfer in SS muscle after RC injury, compared with the control, at both 2 and 6 weeks after TT+DN. BFR-treated mice had significantly reduced muscle atrophy, fatty infiltration, and fibrosis after RC injury. They also observed a significant improvement in forepaw weightbearing ratio and ipsilateral forepaw stride length at 6 weeks after injury in BFR-treated mice compared with controls. CONCLUSION: BFR significantly improves muscle quality and shoulder function after RC injury. These effects occur alongside increased mitochondrial transfer from FAPs to myocytes. CLINICAL RELEVANCE: Understanding the mechanism of BFR by which BFR enhances muscle regeneration could pave the way for its use as a novel rehabilitation strategy to improve recovery in patients with RC injuries and other muscle-related conditions.