Parathyroid Hormone Inhibits Fatty Infiltration and Muscle Atrophy After Rotator Cuff Tear by Browning of Fibroadipogenic Progenitors in a Rodent Model

Progressive fatty infiltration and muscle atrophy after rotator cuff tears lead to tendon repair failure and poor outcomes. Fibro-adipogenic progenitors (FAPs) are involved in fatty infiltration and muscle homeostasis of skeletal muscle. Inducing FAP differentiation into brown adipocyte-like "beige adipocytes" suppresses fatty infiltration and muscle atrophy.Parathyroid hormone (PTH) suppresses fatty infiltration and muscle atrophy after rotator cuff tears in a rat model by browning of FAPs.Controlled laboratory study.PTH was administered subcutaneously for 4 or 8 weeks to a rotator cuff tear model in rats. After treatment, fatty infiltration of supraspinatus muscles was assessed using Oil Red O staining and muscle atrophy using wet muscle weight and muscle fiber cross-sectional area. Costaining of platelet-derived growth factor receptor α (FAP marker) and uncoupling protein 1 (browning marker) was performed to confirm FAP browning by PTH. Mouse-isolated FAPs were cultured with PTH and evaluated for browning-related gene expression and adipogenic differentiation using BODIPY staining. Myogenic differentiation of C2C12 myoblasts was evaluated using coculture of PTH-treated browning FAPs with C2C12.PTH inhibited fatty infiltration after rotator cuff tear at 8 weeks. Rotator cuff wet muscle loss of PTH-treated rats was inhibited at 4 and 8 weeks. Furthermore, PTH-treated rats demonstrated larger myofiber cross-sectional area than did untreated rats at 4 and 8 weeks. Costaining indicated colocalization of platelet-derived growth factor receptor α and uncoupling protein 1 and promoted PTH-induced FAP browning. PTH increased the expression of browning-related genes in FAPs and suppressed fat droplet accumulation in vitro. Coculture with PTH-treated FAPs promoted C2C12 cell differentiation into myotubes.PTH induced FAP-derived beige adipocytes by upregulating browning-related gene expression, and the browning effect of PTH on FAPs inhibited fatty infiltration and muscle atrophy in the rat rotator cuff tear model. PTH might have potential as a therapeutic drug for fatty infiltration and muscle atrophy after rotator cuff tears.PTH may expand treatment options for rotator cuff tears by reducing fatty infiltration and muscle atrophy after rotator cuff tears by browning of FAPs.