Liraglutide (Hybio)

Fatty infiltration (FI) and muscle atrophy following rotator cuff (RC) tears are largely irreversible and are major determinants of poor surgical outcomes, increased re-tear risk, and long-term functional disability. No pharmacologic therapies have been validated to prevent or reverse these degenerative changes. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), including liraglutide, have demonstrated antiadipogenic and tissue-preserving effects in other organ systems, suggesting potential application in RC-related muscle degeneration. We hypothesized that systemic liraglutide administration would attenuate FI, preserve muscle morphology, and improve functional outcomes in a rat model of chronic RC tear without tendon repair.

To evaluate the effects of systemic liraglutide administration on FI, muscle morphology, and functional outcomes in a rat model of chronic RC tear without tendon repair.

A controlled laboratory study.

Adult male Sprague-Dawley rats underwent unilateral supraspinatus tendon transection with interposition of a silicone tube to prevent tendon-to-bone healing. Animals were randomly assigned to receive intraperitoneal liraglutide (250 ㎍/kg/d) or saline for 4 weeks, starting 2 weeks postinjury. At 6 weeks postsurgery, FI was assessed using Oil Red O staining, muscle morphology was examined via hematoxylin-eosin histology, and passive shoulder range of motion was measured with a goniometer. Neuromuscular function was evaluated through compound muscle action potential recordings, and FI was quantified as the percentage of red-stained FI area using ImageJ software with a uniform color-threshold algorithm.

GLP-1RA significantly reduced FI compared with controls (Oil Red O-positive area: 1.11 ± 0.75% vs. 11.82 ± 3.89%, P < .001) and markedly decreased adipocyte deposition on H&E staining. Passive internal rotation was preserved (79 ± 38° vs. 70 ± 2°, P < .001), as was external rotation (55 ± 2° vs. 48 ± 3°, P < .001). Compound muscle action potential amplitudes were significantly greater in the liraglutide group (19.43 ± 8.77 mV vs. 7.61 ± 3.15 mV, P = .028).

Systemic liraglutide administration attenuated chronic muscle degeneration after RC tear by limiting FI, preserving muscle fiber morphology, maintaining joint mobility, and supporting neuromuscular function. These findings provide preclinical justification for therapeutic repositioning of GLP-1RAs in musculoskeletal disorders characterized by irreversible fatty degeneration.

Emerging data suggest more young women than men are prescribed weight loss pharmacotherapies targeting the glucagon‐like peptide‐1 receptor (GLP‐1R). However, preclinical literature has largely used male animals to characterize the neural mechanisms underlying the weight loss abilities of GLP‐1R agonists (GLP‐1RAs), highlighting a need for female‐specific investigations. Recently, we described data pointing to the female estrous cycle as a possible moderator of GLP‐1RA's effects in rats. Expression of brainstem Glp1r and the GLP‐1 precursor gene, Gcg , increased during two estrous phases, proestrus and estrus (P/E), compared to males and compared to other phases, metestrus and diestrus (M/D). On this basis, we hypothesized that the weight‐reducing effects of GLP‐1RAs may be potentiated during P/E.

In separate experiments, we determined whether timing administration of acute liraglutide or chronic semaglutide to either P/E or M/D would moderate food intake and weight loss in female rats maintained on a high fat diet. We also used qPCR to explore estrous cycle‐dependent variation in Glp1r within widely distributed nuclei relevant to energy balance control.

GLP‐1RA administration during P/E, compared to M/D, enhanced the intake‐suppressive effects of liraglutide and semaglutide. Moreover, semaglutide administered only during P/E led to greater body weight loss compared to M/D‐administered semaglutide. We also observed greater Glp1r expression in P/E compared to M/D in multiple nuclei.

GLP‐1RAs administered in P/E lead to significantly greater body weight loss via reduction in food intake. Collectively, these data may have translational implications for the timing of GLP‐1RA administration across the menstrual cycle.