AMPK is mitochondrial medicine for neuromuscular disorders

• Published in: Trends in molecular medicine Vol. 29; no. 7; pp. 512 - 529
• Main Authors: Mikhail, Andrew I., Ng, Sean Y., Mattina, Stephanie R., Ljubicic, Vladimir
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.07.2023
• Subjects: Duchenne muscular dystrophy; mitophagy; myotonic dystrophy type 1; skeletal muscle; spinal muscular atrophy; mitophagy; spinal muscular atrophy; skeletal muscle; Duchenne muscular dystrophy; myotonic dystrophy type 1
• ISSN: 1471-4914; 1471-499X
• DOI: 10.1016/j.molmed.2023.03.008

Mitochondrial stress is a common characteristic of the most prevalent neuromuscular disorders (NMDs) in children and adults, namely Duchenne muscular dystrophy (DMD), myotonic dystrophy type 1 (DM1), and spinal muscular atrophy (SMA), which are otherwise distinct conditions.AMP-activated protein kinase (AMPK) regulates mitochondrial biogenesis, while rapidly emerging research also implicates the kinase in organelle dynamics and mitophagy.AMPK stimulation in preclinical models of DMD, DM1, and SMA, as well as in patients, using pharmacological or physiological interventions, targets mitochondrial stress and results in clinically meaningful improvements in neuromuscular function and health. Duchenne muscular dystrophy (DMD), myotonic dystrophy type 1 (DM1), and spinal muscular atrophy (SMA) are the most prevalent neuromuscular disorders (NMDs) in children and adults. Central to a healthy neuromuscular system are the processes that govern mitochondrial turnover and dynamics, which are regulated by AMP-activated protein kinase (AMPK). Here, we survey mitochondrial stresses that are common between, as well as unique to, DMD, DM1, and SMA, and which may serve as potential therapeutic targets to mitigate neuromuscular disease. We also highlight recent advances that leverage a mutation-agnostic strategy featuring physiological or pharmacological AMPK activation to enhance mitochondrial health in these conditions, as well as identify outstanding questions and opportunities for future pursuit.