Sex Hormone-Binding Globulin Limits Glucocorticoid-Induced Muscle Wasting by Preserving Estrogen-Dependent Repression of Catabolic Signaling

Abstract

Aim

Chronic glucocorticoid (GC) therapy induces severe metabolic complications, notably secondary sarcopenia driven by excessive glucocorticoid receptor (GR)-mediated catabolism. Although sex steroids protect skeletal muscle metabolism, the role of sex hormone-binding globulin (SHBG), the primary determinant of sex steroid bioavailability, in modulating local endocrine crosstalk under GC stress remains unknown.

Methods

We evaluated the clinical correlation between serum SHBG and endocrine factors in a rheumatology cohort frequently exposed to GC. To establish causality and underlying mechanisms, male and female human SHBG-transgenic (hSHBG-Tg) mice, with or without gonadectomy, and C2C12 myoblasts were challenged with dexamethasone (DXM) to simulate GC-induced muscle atrophy.

Results

In patients with high cumulative GC exposure (≥ 10,000 mg), circulating SHBG strongly inversely correlated with serum myostatin (r = −0.7153, p = 0.0076). In mice, hSHBG-Tg significantly rescued DXM-induced loss of muscle mass (quadriceps, gastrocnemius, tibialis anterior) and grip strength in females; notably, this protection was entirely abolished by ovariectomy. Mechanistically, hSHBG-Tg blunted GR Ser211 phosphorylation and downregulated the ubiquitin ligases Fbxo32 and Trim63, while preserving estrogen receptor (ER) target genes (Tff1 and Pgr). In vitro, estradiol antagonized DXM-induced Trim63 transcription via ER, and co-treatment with SHBG sustained this anti-catabolic effect by extending estradiol bioavailability.

Conclusions

SHBG acts as a promoter of estrogen bioavailability that coordinates a protective endocrine crosstalk, counteracting GR-driven catabolism in female skeletal muscle. These findings identify SHBG as a key metabolic determinant and a promising therapeutic target to prevent corticosteroid-induced muscle wasting.