Methionine adenosyltransferase2A inhibition restores metabolism to improve regenerative capacity and strength of aged skeletal muscle

Abstract

We investigate the age-related metabolic changes that occur in aged and rejuvenated myoblasts using in vitro and in vivo models of aging. Metabolic and signaling experiments reveal that human senescent myoblasts and myoblasts from a mouse model of premature aging suffer from impaired glycolysis, insulin resistance, and generate Adenosine triphosphate by catabolizing methionine via a methionine adenosyl-transferase 2A-dependant mechanism, producing significant levels of ammonium that may further contribute to cellular senescence. Expression of the pluripotency factor NANOG downregulates methionine adenosyltransferase 2 A, decreases ammonium, restores insulin sensitivity, increases glucose uptake, and enhances muscle regeneration post-injury. Similarly, selective inhibition of methionine adenosyltransferase 2 A activates Akt2 signaling, repairs pyruvate kinase, restores glycolysis, and enhances regeneration, which leads to significant enhancement of muscle strength in a mouse model of premature aging. Collectively, our investigation indicates that inhibiting methionine metabolism may restore age-associated impairments with significant gain in muscle function.

Identification of a Sonically Activated Degrader of Methionine Adenosyltransferase 2A by an in Silico Approach Assisted with the Hole–Electron Analysis

“…Through a similar molecular engineering strategy, more small molecule degraders targeting other pathogenic proteins could be developed in the future. [1,4]oxazin-8-amine 8 (0.09 g, 0.3 mmol), and PdCl 2 (dppf) DCM (0.02g, 0.03 mmol) in 3 mL of mixed solvent of dioxane/H 2 O (2:1) was stirred at 90 °C for 5 h then concentrated under reduced pressure, the crude residue was purified by flash column chromatography on silica gel chromatography to give the desired product in 20% yield, HPLC purity is >95%. 1 H NMR (500 MHz, chloroform-d) δ 8.67 (s, 1H), 7.71 (s, 1H), 7.32 (dd, J = 8.3, 1.9 Hz, 1H), 7.27 (s, 1H), 7.23 (s, 3H), 7.22 (d, J = 2.2 Hz, 1H), 6.72−6.40 (m, 2H), 4.42 (dd, J = 10.2, 3.4 Hz, 1H), 4.15 (q, J = 7.0 Hz, 2H), 3.64− 3.46 (m, 2H), 3.39 (t, J = 9.8 Hz, 1H), 3.23 (td, J = 9.2, 7.1 Hz, 1H), 2.19−1.91 (m, 3H), 1.48−1.37 (m, 1H), 1.25 (t, J = 7.0 Hz, 3H).…”

“…The metabolic enzyme methionine adenosyltransferase 2A (MAT2A), which plays a vital role in metabolism and epigenetic regulation, is overexpressed in a variety of human tumors including colorectal cancer, hepatocellular carcinoma, gastric cancer, and leukemia . MTA2A has attracted intense attention in drug discovery since the evidence that MAT2A depletion induced by RNA interference leads to a selective antiproliferation effect, namely synthetic lethality, in cancers that lack a separate metabolic gene of methylthioadenosine phosphorylase (MTAP). , Deletion of MTAP gene was rare in normal tissues but frequently appears in human cancers .…”

S-adenosyl-L-methionine Supplementation Alleviates Aortic Dissection by Decreasing Inflammatory Infiltration

“…The hydrolysis of SAH then yields homocysteine and adenosine, ultimately leading to the regeneration of methionine and SAM. The balance between SAM and SAH, re ected in the SAM/SAH ratio, is crucial for maintaining appropriate cellular methylation dynamics 43 .…”

Metabolic pathways in immune senescence and inflammaging: Novel therapeutic strategy for chronic inflammatory lung diseases. An EAACI position paper from the Task Force for Immunopharmacology

“…25,26 However, every cell type can have its own senescent metabolic signature, even with decreased glycolysis or increased OXPHOS. [26][27][28]…”