AMPK Complex Activation Promotes Sarcolemmal Repair in Dysferlinopathy

Abstract

Mutations in dysferlin are responsible for a group of progressive, recessively inherited muscular dystrophies known as dysferlinopathies. Using recombinant proteins and affinity purification methods combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS), we found that AMP-activated protein kinase (AMPK)γ1 was bound to a region of dysferlin located between the third and fourth C2 domains. Using ex vivo laser injury experiments, we demonstrated that the AMPK complex was vital for the sarcolemmal damage repair of skeletal muscle fibers. Injury-induced AMPK complex accumulation was dependent on the presence of Ca 2+ , and the rate of accumulation was regulated by dysferlin. Furthermore, it was found that the phosphorylation of AMPKα was essential for plasma membrane repair, and treatment with an AMPK activator rescued the membrane-repair impairment observed in immortalized human myotubes with reduced expression of dysferlin and dysferlin-null mouse fibers. Finally, it was determined that treatment with the AMPK activator metformin improved the muscle phenotype in zebrafish and mouse models of dysferlin deficiency. These findings indicate that the AMPK complex is essential for plasma membrane repair and is a potential therapeutic target for dysferlinopathy.

Inhibition of the immunoproteasome modulates innate immunity to ameliorate muscle pathology of dysferlin-deficient BlAJ mice

“…Interestingly, we found an increase of the ratio pP38/P38 and pAKT/AKT in 12 m BlAJ vs 12 m WT mice as previously recognized in several murine dystrophic animal models [ 57 , 58 ]. Moreover, downregulation of the ratio pAMPKα/AMPKα was observed in 12 m BlAJ vs 12 m WT mice according to the literature describing the role of pAMPKα in plasma membrane repair of dysferlin-deficient myotubes [ 59 ]. Since the muscle microenvironment created by trained innate immune cells may have profound effects on T cell responses, such as altering the differentiation, polarization and function of T cell subtypes, we further characterized T cell repertoire through FACS analysis in 12 m BlAJ limb muscles.…”

Role of DYSF Genetic Variant in Limb Girdle Muscular Dystrophy: A Case Report

“…As exome sequencing clinical usage becomes more widespread, the time to diagnosis is decreasing significantly, resulting in improved treatment strategies and management of genetic disorders. A study reported in 2020 demonstrated that AMP-activated protein kinase (AMPK) γ1 plays a key role in fixing the plasma membrane, and AMPK is essential for possible treatments (12). Another recent study on Korean populations demonstrated that the most common pathogenic variants are nonsense mutations for dysferlinopathies, and about 50% of the studied patients had one nonsense variant.…”

The Function of Metformin in Aging-Related Musculoskeletal Disorders

“…The combination of metformin and leucine can positively affect aging muscle function by increasing satellite cell content and modulating collagen remodeling ( Petrocelli et al, 2021 ). Moreover, metformin can attenuate the muscle inflammatory response in diabetic patients ( Peixoto et al, 2017 ), promote the repair of myofilament damage in skeletal muscle fibers ( Ono et al, 2020 ; Dong et al, 2021 ), and protect the respiratory capacity of skeletal muscle by counteracting oxidative stress damage ( Kane et al, 2010 ). However, Stockinger et al (2017) discovered that metformin did not significantly affect the aging of the neuromuscular junction.…”