Parathyroid hormone promotes induction of beige adipocytes and reversibly ameliorates muscle quality and atrophy following chronic rotator cuff tear in a rat model

Ryosuke Iio; Tomoya Manaka; Naoki Takada; Kumi Orita; Katsumasa Nakazawa; Yoshihiro Hirakawa; Yoichi Ito; Hiroaki Nakamura

doi:10.1016/j.jse.2024.03.068

Parathyroid hormone promotes induction of beige adipocytes and reversibly ameliorates muscle quality and atrophy following chronic rotator cuff tear in a rat model

J Shoulder Elbow Surg. 2024 May 27:S1058-2746(24)00385-9. doi: 10.1016/j.jse.2024.03.068. Online ahead of print.

Authors

Ryosuke Iio¹, Tomoya Manaka², Naoki Takada³, Kumi Orita³, Katsumasa Nakazawa¹, Yoshihiro Hirakawa³, Yoichi Ito⁴, Hiroaki Nakamura³

Affiliations

¹ Department of Orthopedic Surgery, Graduate School of Medicine, Osaka City University, Osaka, Japan; Department of Orthopedic Surgery, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan.
² Department of Orthopedic Surgery, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan. Electronic address: manakaT@omu.ac.jp.
³ Department of Orthopedic Surgery, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan.
⁴ Ito Clinic, Osaka Shoulder Center, Matsubara-city, Osaka, Japan.

PMID: 38810913
DOI: 10.1016/j.jse.2024.03.068

Abstract

Background: Fatty infiltration (FI) and muscle atrophy (MA) in the rotator cuff muscles following rotator cuff tears (RCT) persist postrepair, increasing the risk of re-tears. Brown adipocyte-like "beige adipocytes" are expected to have a therapeutic effect on intramuscular FI and MA due to their lipolytic activity and the muscle regenerative effects of their secreted factors. However, whether parathyroid hormone (PTH) ameliorates the already advanced FI and MA remains unknown. Therefore, this study aimed to clarify whether PTH promotes the expression of beige adipocytes and ameliorates advanced FI and MA following chronic RCT in rats.

Methods: Supraspinatus muscles were harvested from rats with chronic RCT after 4 or 8 weeks of PTH treatment and compared to those in the control group or to those at the start of treatment. FI was assessed by Oil Red O staining, and the staining area was evaluated as a percentage of the muscle cross-sectional area. MA was evaluated by measuring muscle wet weight and cross-sectional area of muscle fiber. Beige adipocyte expression was evaluated by immunostaining for uncoupling protein 1 (UCP1). Fibro-adipogenic progenitors (FAPs) were separated from muscle-injured mice. We assessed whether PTH could diminish fat droplet accumulation by promoting the differentiation of FAPs into beige adipocytes.

Results: After 4 weeks, PTH reduced the area fraction of FI in the rat supraspinatus muscle following chronic RCT compared with that at the beginning of treatment (P = .028). In addition, PTH increased wet muscle mass (P < .001), and muscle fiber cross-sectional area (P = .018) compared with measurements at the start of treatment. PTH administration promoted the expression of UCP1, a beige adipocyte marker, in the supraspinatus muscle (P = .019). PTH increased gene expression of beige adipocyte-related markers and suppressed fat droplet accumulation even after adipogenic differentiation of FAPs (P = .004) but did not reduce fat droplets that had already accumulated in in vitro experiments.

Conclusions: PTH facilitated beige adipocyte expression and reversibly ameliorated muscle quality and atrophy following chronic RCT by hindering fat droplet accumulation and facilitating muscle regeneration. Therefore, PTH may be a medical treatment for FI and MA following RCT, leading to expanded rotator cuff repair indications.

Keywords: Rotator cuff muscle; beige adipocytes; fatty infiltration; fibro-adipogenic progenitors; muscle atrophy; parathyroid hormone.