Defining Endogenous Mitochondrial Transfer in Muscle After Rotator Cuff Injury.

BACKGROUND: Rotator cuff muscle degeneration leads to poor clinical outcomes for patients with rotator cuff tears. Fibroadipogenic progenitors (FAPs) are resident muscle stem cells with the ability to differentiate into fibroblasts as well as white and beige adipose tissue. Induction of the beige adipose phenotype in FAPs has been shown to improve muscle quality after rotator cuff tears, but the mechanisms of how FAPs exert their beneficial effects have not been fully elucidated. PURPOSE: To study the horizontal transfer of mitochondria from FAPs to myogenic cells and examine the effects of ß-agonism on this novel process. STUDY DESIGN: Controlled laboratory study. METHODS: In mice that had undergone a massive rotator cuff tear, single-cell RNA sequencing was performed on isolated FAPs for genes associated with mitochondrial biogenesis and transfer. Murine FAPs were isolated by fluorescence-activated cell sorting and treated with a ß-agonist versus control. FAPs were stained with mitochondrial dyes and cocultured with recipient C2C12 myoblasts, and the rate of transfer was measured after 24 hours by flow cytometry. PdgfraCreERT/MitoTag mice were generated to study the effects of a rotator cuff injury on mitochondrial transfer. PdgfraCreERT/tdTomato mice were likewise generated to perform lineage tracing of PDGFRA+ cells in this injury model. Both populations of transgenic mice underwent tendon transection and denervation surgery, and MitoTag-labeled mitochondria from Pdgfra+ FAPs were visualized by fluorescent microscopy, spinning disk confocal microscopy, and 2-photon microscopy; overall mitochondrial quantity was compared between mice treated with ß-agonists and dimethyl sulfoxide. RESULTS: Single-cell RNA sequencing in mice that underwent rotator cuff tear demonstrated an association between transcriptional markers of adipogenic differentiation and genes associated with mitochondrial biogenesis. In vitro cocultures of murine FAPs with C2C12 cells revealed that treatment of cells with a ß-agonist increased mitochondrial transfer compared to control conditions (17.8% ± 9.9% to 99.6% ± 0.13% P < .0001). Rotator cuff injury in PdgfraCreERT/MitoTag mice resulted in a robust increase in MitoTag signal in adjacent myofibers compared with uninjured mice. No accumulation of tdTomato signal from PDGFRA+ cells was seen in injured fibers at 6 weeks after injury, suggesting that FAPs do not fuse with injured muscle fibers but rather contribute their mitochondria. CONCLUSION: The authors have described a novel process of endogenous mitochondrial transfer that can occur within the injured rotator cuff between FAPs and myogenic cells. This process may be leveraged therapeutically with ß-agonist treatment and represents an exciting target for improving translational therapies available for rotator cuff muscle degeneration. CLINICAL RELEVANCE: Promoting endogenous mitochondrial transfer may represent a novel translational strategy to address muscle degeneration after rotator cuff tears.

Effect of obesity on short- and long-term complications of shoulder arthroplasty.

BACKGROUND: The proportion of patients undergoing total shoulder arthroplasty (TSA) with obesity continues to grow every year in the United States. Although comorbid obesity is common among TSA patients, the relationship of obesity on medical and surgical complications remains debated. The goal of this study was to evaluate a national database for postoperative medical and surgical complications in patients undergoing TSA with comorbid obesity. METHODS: Patients undergoing anatomic and reverse TSA were studied in the PearlDiver database. Current Procedural Terminology (CPT) and International Classification of Diseases (ICD) codes were used to compare patients with and without preoperative obesity who underwent TSA, and they were stratified based on body mass index (BMI) into nonobese, obese, morbidly obese, and superobese. A matched comparison was performed at a 1:1 ratio based on age, sex, diabetes, smoking, tobacco use, and Charlson Comorbidity Index. RESULTS: From 2010 to 2020, a total of 113,634 patients undergoing anatomic or reverse TSA were identified in a national database. During this time, the percentage of TSA patients with obesity increased every year. Matched cohort analysis demonstrated higher odds of readmission, deep vein thrombosis and pulmonary embolism, superficial infection, and prosthetic joint infection at 90 days postoperatively in the obesity group. There were no increased odds of mechanical complications or revision surgery at 2 years in the obesity group when matched to nonobese patients with similar comorbidities. CONCLUSION: The number of patients undergoing TSA with obesity is rising. Medical complications and infection after TSA are greater in obese patients even when matching for medical comorbidities, age, and sex, and rates of complication increase as BMI increases. Obesity is not an independent risk factor for mechanical surgical complications and revision surgery, and the relatively higher rates are likely due to an increased burden of other comorbidities. Surgeons should counsel obese patients appropriately regarding their perioperative risk of medical complication, but they should not expect higher rates of mechanical complication or revision surgery at 2-year follow-up when compared to a matched control group with similar comorbidities.