Aging is the primary risk factor for most chronic diseases and is characterized in striated muscle by progressive functional decline, mitochondrial dysfunction, and chronic inflammation. The miR-128-1 locus resides within a positively selected haplotype on chromosome 2q21.3 associated with variation in grip strength, pulmonary function, and cardiometabolic traits in humans. Here, we show that antisense oligonucleotide-mediated inhibition of miR-128-3p restores muscle mass and function in aged mice, improves cardiac function while limiting adverse remodeling following myocardial infarction, and ameliorates skeletal and cardiac muscle pathology in mouse and pig models of Duchenne muscular dystrophy. Across these contexts, miR-128-3p inhibition induces a conserved transcriptional response characterized by activation of mitochondrial programs and suppression of inflammatory and fibrotic signaling, resembling the effects of established longevity interventions. These findings identify miR-128-3p as a regulator of a conserved aging-associated program and establish its inhibition as a strategy to restore tissue function across aging-related muscle pathologies. Graphical Abstract Highlights miR-128 loci associate with reduced grip strength; miR-128-1 also with lung function. miR-128-3p drives mitochondrial dysfunction and inflammation in striated muscle. Anti-miR-128 ASO rescues function in aged, infarcted, and dystrophic muscle. Inhibition recapitulates transcriptional effects of longevity interventions.
Melissa A. Boldridge, Lei Xu, Xiaoyin Wang et al.· bioRxiv· 0 citations
Pseudomonas aeruginosa (PA) uses its quorum-sensing molecule 2’-aminoacetophenone (2-AA) to modulate host mitochondrial activity. This study investigates how 2-AA—driven host metabolic reprogramming contributes to macrophage dysfunction and supports bacterial persistence.
We used biochemical and molecular assays to show that 2-AA induced host lactate augmentation. Immunoprecipitation identified proteins involved in histone lactylation (Kla), while CUT&RUN and transcriptomics studies deciphered gene regulation and molecular anergy.
Mechanistically, 2-AA disrupts the ESRRA—PPARGC1α regulatory axis, leading to the downregulation of the mitochondrial pyruvate carrier (MPC1). This impairment affects pyruvate transport into mitochondria, rewiring cellular metabolism to a glycolytic state, leading to increased lactate dehydrogenase A (LDHA) activity, elevated and sustained lactate levels in PA-infected immune cells and host tissues, and Kla. Genome-wide profiling of H3 lysine 18 lactylation (H3K18la) demonstrated distinct chromatin modification at regulatory regions, indicating novel epigenetic regulation by lactylation. The 2-AA-mediated H3K18la involves the GTP-specific succinyl-CoA synthetase (GTPSCS) and its interaction with histone lactyl-transferases CREB-binding protein (CBP) and p300. In agreement with H3k18la signatures, transcriptomic profiling of wild-type PA and its 2-AA-deficient mutant revealed regulatory pathways modulating immune and metabolic responses. Functionally, enhanced H3K18la favors a tolerogenic macrophage phenotype that supports intracellular bacterial survival. Conversely, inhibiting lactate accumulation or blocking 2-AA synthesis diminishes H3K18la and enhances bacterial clearance.
Collectively, these findings uncover a previously unrecognized QS-regulated metabolic—epigenetic axis through which PA manipulates host immunity, highlighting lactate metabolism as a potential therapeutic target for combating chronic Pseudomonas infections.
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Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)
Arijit Chakraborty, Arijit Chakraborty, Shifu Aggarwal et al.· Journal of Immunology· 0 citations
An input-specific translatome screen is designed to identify regulators of experience-dependent PV IN plasticity genes (XPGs) in the CA3/CA2 subregion of adult hippocampus and shows that experience-dependent PV IN plasticity is a convergent mechanism for NDD risk genes that can be re-instated in adulthood to reverse developmental deficits in circuitry, network excitability and cognition.
Yu-Tzu Shih, J. Alipio, Z. Klaft et al.· Nature· 2 citations
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