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Impaired skeletal muscle stem cell (MuSC) function has long been suspected to contribute to the pathogenesis of muscular dystrophy (MD). Here we describe that defects in the endothelial cell (EC) compartment of the perivascular stem cell niche in three different types of MD are associated with inefficient mobilization of MuSCs following tissue damage. Using chemoinformatic analysis, we identified the 13 amino acid form of the peptidic hormone apelin (AP-13) as a candidate for systemic stimulation of skeletal muscle ECs. In dystrophic mice, administration of AP-13 generates a pro-myogenic EC-rich niche that supports MuSC function and markedly improves tissue regeneration, muscle strength, and physical performance. Moreover, we demonstrate that EC specific knockout of the AP-13 receptor leads to regenerative defects that phenocopy major pathological features of MD. Altogether, we provide in vivo proof-of-concept that enhancing endogenous repair by targeting the perivascular niche is a viable therapeutic avenue for MD and characterize AP-13 as a novel drug candidate for systemic treatment of stem cell dysfunction.

BackgroundShoulder pain secondary to rotator cuff tendinopathy affects a large proportion of patients in orthopedic surgery practices. Corticosteroid injections are a common intervention proposed for these patients. The clinical evaluation of a response to corticosteroid injections is usually based only on the patient’s self-evaluation of his function, activity, and pain by multiple questionnaires with varying metrological qualities. Objective measures of upper extremity functions are lacking, but wearable sensors are emerging as potential tools to assess upper extremity function and activity.ObjectiveThis study aimed (1) to evaluate and compare test-retest reliability and sensitivity to change of known clinical assessments of shoulder function to wrist-based accelerometer measures and visual analog scales (VAS) of shoulder activity during daily living in patients with rotator cuff tendinopathy convergent validity and (2) to determine the acceptability and compliance of using wrist-based wearable sensors.MethodsA total of 38 patients affected by rotator cuff tendinopathy wore wrist accelerometers on the affected side for a total of 5 weeks. Western Ontario Rotator Cuff (WORC) index; Short version of the Disability of the Arm, Shoulder, and Hand questionnaire (QuickDASH); and clinical examination (range of motion and strength) were performed the week before the corticosteroid injections, the day of the corticosteroid injections, and 2 and 4 weeks after the corticosteroid injections. Daily Single Assessment Numeric Evaluation (SANE) and VAS were filled by participants to record shoulder pain and activity. Accelerometer data were processed to extract daily upper extremity activity in the form of active time; activity counts; and ratio of low-intensity activities, medium-intensity activities, and high-intensity activities.ResultsDaily pain measured using VAS and SANE correlated well with the WORC and QuickDASH questionnaires (r=0.564-0.815) but not with accelerometry measures, amplitude, and strength. Daily activity measured with VAS had good correlation with active time (r=0.484, P=.02). All questionnaires had excellent test-retest reliability at 1 week before corticosteroid injections (intraclass correlation coefficient [ICC]=0.883-0.950). Acceptable reliability was observed with accelerometry (ICC=0.621-0.724), apart from low-intensity activities (ICC=0.104). Sensitivity to change was excellent at 2 and 4 weeks for all questionnaires (standardized response mean=1.039-2.094) except for activity VAS (standardized response mean=0.50). Accelerometry measures had low sensitivity to change at 2 weeks, but excellent sensitivity at 4 weeks (standardized response mean=0.803-1.032).ConclusionsDaily pain VAS and SANE had good correlation with the validated questionnaires, excellent reliability at 1 week, and excellent sensitivity to change at 2 and 4 weeks. Daily activity VAS and accelerometry-derived active time correlated well together. Activity VAS had excellent reliability, but moderate sensitivity to change. Accelerometr...