PGE2 Ameliorates Aging-Aggravated Rotator Cuff Muscle Atrophy.

Abstract

Background: The aging-related escalation of muscle degeneration impacts the structure and function of rotator cuff muscles, contributing to spontaneous and tear-induced muscle atrophy. This study investigated how prostaglandin E2 (PGE2), a regulator of muscle regeneration, influences muscular structure and mitochondrial function in aged mice by using SW033291 to inhibit PGE2 degradation, revealing potential therapeutic pathways for mitigating rotator cuff muscle deterioration.

Methods: A total of 20 young (5 to 6-month-old) and 100 aged (18 to 20-month-old) female C57BL/6J mice were divided into 2 groups: the first group included young, aged, and aged+SW033291 subgroups and was used to study sarcopenia, and the second group consisted of tear, tear+repair, and tear+repair+SW033291 subgroups and was used to examine the outcomes following a rotator cuff tear (RCT). Tissue staining, muscle mass assessments, functional assays, and mitochondrial function tests were performed.

Results: Rotator cuff muscle degeneration was observed in the setting of natural aging and in the setting of an RCT. These conditions together worsened muscle atrophy and fatty infiltration into the muscle, with the aged tear group demonstrating a decrease in muscle mass from a mean and standard deviation of 45.45 ± 4.04 to 25.18 ± 1.82 mg (p < 0.001) and a reduction in fiber cross-sectional area (CSA) from 1,697.3 ± 108.4 to 1,263.0 ± 56.8 μm2 (p < 0.001). This was linked to increased 15-prostaglandin dehydrogenase (15-PGDH) activity and a reduction in PGE2 levels in the aged tear group (from 2.897 ± 0.177 to 1.873 ± 0.179 ng/g muscle; p < 0.001). SW033291 treatment increased the level of PGE2, reversing muscle atrophy by mitigating mitochondrial dysfunction in both models, as demonstrated by a muscle mass of 33.50 ± 3.05 mg and a CSA of 1,423.6 ± 81.3 μm2 in the presence of both conditions.

Conclusions: These findings support the hypothesis that elevated PGE2 levels can improve muscle health by reversing mitochondrial dysfunction, offering a strategy to combat sarcopenia and to enhance rotator cuff repair.

Clinical relevance: Large or massive RCTs are associated with muscle atrophy, a higher retear rate, and suboptimal surgical outcomes, especially in elderly patients. This study showed that the occurrence of rotator cuff muscle degeneration and muscular mitochondrial dysfunction in both the natural aging and RCT mouse models was mitigated by enhanced PGE2 levels. This finding demonstrates the efficacy of the application of a 15-PGDH inhibitor and suggests a possible new therapeutic approach.