AJSM - 2026-04-01 - Journal Article
Blood Flow Restriction Therapy Stimulates Intercellular Mitochondria Transfer and Improves Muscle Regeneration and Shoulder Function in a Murine Rotator Cuff Injury Model.
Milan N, Wague A, Sang L, Youn A, Sadjadi R, Samimi Y, Montenegro C, Lizarraga M, Lau J, Basbaum AI, Davies MR, Kim HT, Feeley BT, Weinrich JAP, Liu X
Topics
Key Takeaway
BFR stimulates FAP-to-myocyte mitochondrial transfer within 1 day in murine supraspinatus muscle and reduces fatty infiltration, fibrosis, and muscle atrophy at 6 weeks after massive rotator cuff tear with denervation.
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Summary
This controlled laboratory study used Prrx1-Cre/MitoTag reporter mice to determine whether BFR induces FAP-to-myocyte mitochondrial transfer in healthy and RC-injured supraspinatus muscle. BFR initiated mitochondrial transfer within 1 day and the effect persisted up to 3 days; in the TT+DN massive tear model, BFR-treated mice showed significantly reduced fatty infiltration, fibrosis, and atrophy versus controls at both 2 and 6 weeks. Functional outcomes (Blackbox system) demonstrated improved forepaw weightbearing ratio and ipsilateral stride length at 6 weeks in BFR-treated animals.
Key Limitation
The murine forelimb is not biomechanically analogous to the human shoulder, and the mandatory denervation component of the injury model limits direct translation to clinical RC tears where neurologic injury is not a consistent feature.
Original 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.