Metformin inhibits muscle atrophy through the PI3K/AKT/mTOR pathway in a rat model of acute rotator cuff tears

Background: Muscle atrophy after the rupture of a rotator cuff (RC) tendon is a major factor that increases the risk of secondary complications and re-rupture. Metformin, a type 2 diabetes treatment, can be used to modulate intracellular signaling pathways that promote muscle growth. This study aimed to verify whether systemic metformin administration could prevent supraspinatus (SS) atrophy after RC rupture in a rat model.

Methods: This study is a comparative animal study aimed at investigating the effects of metformin. Twelve-week-old male Sprague-Dawley rats were used. The metformin group was administered intraperitoneal injection with 50 mg/kg metformin daily for 6 weeks after the RC tendon was cut, while the control group was given 0.9% saline solution. All rats were weighed and sacrificed 6 weeks after their surgery; then, SS were collected, and individual SS weights were measured. The expression of muscle atrophy genes was determined through quantitative reverse transcription polymerase chain reaction, and the amount of signal metabolism regulatory protein was measured by western blotting. Muscle atrophy and fatty infiltration (FI) were evaluated by histological staining.

Results: Six weeks after RC tendon rupture, the SS weight in the metformin group was significantly higher than in the control group. Western blotting analysis revealed that the expression levels of phosphatidylinositol 3-kinase (P = .002), protein kinase B (P = .001), and mammalian targets of rapamycin (P = .009) protein were significantly higher in the metformin group than in the control group. The muscle atrophy-related marker genes Atrogin-1 (P = .036) and MuRF-1 (P < .000) in the metformin group were downregulated. The morphology of the SS, whose atrophy was prevented by metformin, had fewer wide pores and less reduced muscle fiber area than those of the control group. Muscle tissue staining analysis showed that FI was significantly suppressed by systemic metformin administration compared with that of the control group both qualitatively and quantitatively (P = .032). Metformin elicited an FI-suppressing effect by downregulating the adipogenic genes PPAR-γ (P = .001) and C/EBP-α (P< .001).

Conclusions: Metformin significantly prevented SS atrophy by activating the PI3K/AKT/mTOR pathway in an acute RC tear rat model. It also suppressed FI by downregulating adipogenic factors in the late stage of RC tear. These results strongly supported the usefulness of metformin for high-quality muscle preservation after RC rupture in clinical practice.