Targeting Progesterone Receptor Membrane Component 1 to Improve Muscle Development and Glucose Homeostasis

Type 2 diabetes mellitus (T2D) arises from the interplay between peripheral insulin resistance and pancreatic β-cell dysfunction, ultimately leading to impaired glucose utilization and chronic hyperglycemia. Despite therapeutic advances, the multifactorial nature of T2D continues to demand the development of novel treatment strategies. Progesterone receptor membrane component 1 (PGRMC1) has emerged as a potential modulator of metabolic function, though its role in T2D pathogenesis has not been fully elucidated.

To investigate the role of PGRMC1 in T2D, we generated skeletal muscle-specific Pgrmc1 knockout (PKO) mice (ACTA^cre-Pgrmc1^fl/fl). T2D was induced via a high-fat diet combined with streptozotocin (HFD-STZ) or using genetically diabetic (lepr^db/lepr^db; db/db) mice. A small-molecule screen of 330 compounds identified 11α-hydroxyprogesterone (11α-OHP) as a PGRMC1-modulating candidate. The antidiabetic efficacy of 11α-OHP was assessed in vitro and across multiple in vivo diabetic models. Whole-body PKO mice were used to evaluate the systemic consequences of global Pgrmc1 deletion. Glucose tolerance test (GTT), insulin tolerance test (ITT) and modified homeostatic model assessment for insulin resistance (HOMA-IR, 5-h fasting) were used to evaluate glucose metabolism. Real-time cell metabolism analyser (Seahorse analysis) was used for measuring cellular glycolysis.

Skeletal muscle PKO improved glucose clearance in GTT (p < 0.0001) and insulin sensitivity in ITT (p < 0.0001). Skeletal muscle PKO mice under T2D suppressed insulin resistance according to reduced modified HOMA-IR (p < 0.05) and promoted muscle development (quadriceps femoris, gastrocnemius, tibialis anterior muscle and extensor digitorum longus; p < 0.05). Mechanistically, PGRMC1 interacted with PPP2R5D, a PP2A regulatory subunit, which dephosphorylates RSK1. PGRMC1 loss suppressed PP2A activity, increasing RSK1 phosphorylation and activating AKT signalling, thereby enhancing myoblast proliferation (p < 0.05), differentiation (p < 0.01) and glycolysis (p < 0.0001). 11α-OHP facilitated proteasomal degradation of PGRMC1, elevated pAKT levels and improved glucose clearance in GTT (p < 0.0001) and insulin sensitivity in ITT (p < 0.0001) in wild-type mice but not in PKO mice. Notably, 11α-OHP restored glucose clearance in GTT (p < 0.0001) and insulin sensitivity in ITT (p < 0.0001) and increased muscle mass in both HFD-STZ and db/db mice, but its effects were abolished in skeletal muscle PKO mice. Whole-body PKO mice still increased muscle development and metabolic activation, suggesting minimal interference by systemic PKO.

These findings identify skeletal muscle PGRMC1 as a pivotal regulator of glucose metabolism and highlight its inhibition as a promising muscle-targeted therapeutic approach for T2D management.