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Aberrant expression of the double homeobox 4 (<i>DUX4</i>) gene in skeletal muscle predominantly drives the pathogenesis of facioscapulohumeral muscular dystrophy (FSHD). We recently demonstrated that berberine, an herbal extract known for its ability to stabilize guanine–quadruplex structures, effectively downregulates <i>DUX4</i> expression in FSHD patient-derived myoblasts and in mice overexpressing exogenous <i>DUX4</i> after viral vector-based treatment. Here, we sought to confirm berberine’s inhibitory efficacy on <i>DUX4</i> in the widely used FSHD-like transgenic mouse model, ACTA1-MCM/FLExDUX4, where <i>DUX4</i> is induced at pathogenic levels using tamoxifen. Animals repeatedly treated with berberine via intraperitoneal injections for 4 weeks exhibited significant reductions in both mRNA and protein levels of <i>DUX4</i>, and in mRNA expression of murine DUX4-related genes. This inhibition translated into improved forelimb muscle strength and positive alterations in important FSHD-relevant cellular pathways, although its impact on muscle mass and histopathology was less pronounced. Collectively, our data confirm the efficacy of berberine in downregulating <i>DUX4</i> expression in the most relevant FSHD mouse model. However, further optimization of dosing regimens and new studies to enhance the bioavailability of berberine in skeletal muscle are warranted to fully leverage its therapeutic potential for FSHD treatment.