A phlorotannin-rich seaweed extract activates AMPK/PGC-1α signaling and antioxidant defences in skeletal muscle cells.

Sedentary behaviour, ageing and chronic diseases represent major public health burdens associated with impaired skeletal muscle function and increased oxidative stress. Identifying bioactive compounds capable of mimicking the molecular adaptations induced by physical exercise therefore constitutes a relevant pharmacological strategy. Phlorotannins, polyphenolic compounds exclusively biosynthesised by brown macroalgae, are promising candidates owing to their antioxidant and metabolic properties. This study aimed to characterise a phlorotannin-enriched ethyl acetate extract from Halidrys siliquosa (HS extract) and assess its pharmacological properties in L6 rat myoblasts, a well-established skeletal muscle cell model. Chemical profiling by LC-MS and NMR identified carmalol- and fuhalol-type derivatives, two subclasses of phlorotannins, as predominant constituents, with strong radical scavenging activity in the DPPH assay. HS extract was non-cytotoxic at 1 and 10 µg/mL and did not alter basal ROS levels after 24-h treatment. At the molecular level, HS extract significantly increased the P-AMPK/AMPK ratio and PGC-1α transcript levels, two key mediators of exercise-induced metabolic adaptation, and enhanced glutathione peroxidase (GPx) enzymatic activity, indicating reinforced antioxidant defences. In a preventive setting, HS extract pretreatment markedly reduced H₂O₂-induced cell death and ROS overproduction. Collectively, these findings demonstrate that HS extract activates exercise-associated metabolic signaling pathways in rat skeletal muscle cells. These results suggest that HS extract may represent a promising source of bioactive compounds capable of modulating exercise-related molecular responses, warranting further investigation in differentiated muscle models and in vivo studies.