LKB1 Dysregulation in Duchenne Muscular Dystrophy Models: Disease Specificity and Epigenetic Control by HDAC Inhibitors
Brigida Boccanegra, Lisamaura Tulimiero, Raffaella Quarta, Elena Conte, Simonetta Andrea Licandro, Alessandra Decio, Roberta Lenti, Alberto Ladisa, Giorgia Dinoi, Gaia Carbone, Letizia Claudione, Giulia Maria Camerino, Sabata Pierno, Paola Mantuano, Ornella Cappellari, Gianluca Fossati, Christian Steinkühler, Annamaria De LucaABSTRACT
Efficient skeletal muscle contraction requires tight mechano‐metabolic coupling, a process regulated by AMP‐activated protein kinase (AMPK). Duchenne muscular dystrophy (DMD) is characterized by aberrant AMPK activation and disrupted metabolic signaling. This study investigates the expression and regulation of the LKB1–STRADα–MO25 heterotrimeric complex, the primary upstream activator of AMPK, in DMD models. We analyzed muscles from dystrophic mice (BL10 mdx and D2 mdx ) and patient‐derived cells and found significant downregulation of the LKB1 complex across all disease stages in the DMD models, a defect not observed in an amyotrophic lateral sclerosis model. Treatment with the broad‐spectrum HDAC inhibitor vorinostat effectively restored LKB1 expression at both transcript and protein levels in D2 mdx mice. This restoration was mechanistically linked to downregulation of miR‐451, miR‐195, and miR‐17, which function as post‐transcriptional repressors of LKB1. Conversely, the selective HDAC1/2 inhibitor Rodin‐A increased Lkb1 mRNA but failed to rescue protein levels or alter miRNA expression. Our data identify the axis LKB1–STRADα–MO25 as a critical regulatory node that is disrupted in DMD, but remains responsive to epigenetic modulation. These findings suggest that restoring LKB1 activity via HDAC inhibition or miRNA targeting may represent a therapeutic avenue to address dystrophic muscle dysfunction.