Acta physiologica (Oxford, England) · 2026
Sex Hormone-Binding Globulin Limits Glucocorticoid-Induced Muscle Wasting by Preserving Estrogen-Dependent Repression of Catabolic Signaling.
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Park Junyong, Song Ah-Young, Bae Hae-Rahn, Hong Eui-Ju, Lee Sang R
Аннотация
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.
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.