Pyruvate dehydrogenase B regulates myogenic differentiation via the FoxP1–Arih2 axis

Abstract

Background Sarcopenia, the age-related decline in skeletal muscle mass and function, diminishes life quality in elderly people. Improving the capacity of skeletal muscle differentiation is expected to counteract sarcopenia. However, the mechanisms underlying skeletal muscle differentiation are complex, and effective therapeutic targets are largely unknown. Methods The human Gene Expression Omnibus database, aged mice and primary skeletal muscle cells were used to assess the expression level of pyruvate dehydrogenase B (PDHB) in human and mouse aged state. D-Galactose (D-gal)-induced sarcopenia mouse model and two classic cell models (C2C12 and HSkMC) were used to assess the myogenic effect of PDHB and the underlying mechanisms via immunocytochemistry, western blotting, quantitative real-time polymerase chain reaction, RNA interference or overexpression, dual-luciferase reporter assay, RNA sequencing and untargeted metabolomics. ResultsWe identified that a novel target PDHB promoted myogenic differentiation. PDHB expression decreased in aged mouse muscle relative to the young state (À50% of mRNA level, P < 0.01) and increased during mouse and primary human muscle cell differentiation (+3.97-fold, P < 0.001 and +3.79-fold, P < 0.001). Knockdown or overexpression of PDHB modulated the expression of genes related to muscle differentiation, namely, myogenic factor 5 (Myf5) (À46%, P < 0.01 and À27%, P < 0.05; +1.8-fold, P < 0.01), myogenic differentiation (MyoD) (À55%, P < 0.001 and À34%, P < 0.01; +2.27-fold, P < 0.001), myogenin (MyoG) (À60%, P < 0.001 and À70%, P < 0.001; +5.46-fold, P < 0.001) and myosin heavy chain (MyHC) (À70%, P < 0.001 and À69%, P < 0.001; +3.44-fold, P < 0.001) in both C2C12 cells and HSkMC. Metabolomic and transcriptomic analyses revealed that PDHB knockdown suppressed pyruvate metabolism (P < 0.001) and up-regulated ariadne RBR E3 ubiquitin protein ligase 2 (Arih2) (+7.23-fold, P < 0.001) in cellular catabolic pathways. The role of forkhead box P1 (FoxP1) (+4.18-fold, P < 0.001)-mediated Arih2 transcription was the key downstream regulator of PDHB in muscle differentiation. PDHB overexpression improved D-gal-induced muscle atrophy in mice, which was characterized by significant increases in grip strength, muscle mass and mean muscle cross-sectional area (1.19-fold to 1.5-fold, P < 0.01, P < 0.05 and P < 0.001). Conclusions The comprehensive results show that PDHB plays a sarcoprotective role by suppressing the FoxP1-Arih2 axis and may serve as a therapeutic target in sarcopenia.

Metabolic clues to aging: exploring the role of circulating metabolites in frailty, sarcopenia and vascular aging related traits and diseases

“…In addition, pyruvate dehydrogenase kinases (PDKs), which regulate pyruvate’s entry into the tricarboxylic acid cycle, are implicated in muscle formation and atrophy, making them potential therapeutic targets for sarcopenia ( Kim et al, 2023 ). An experimental study also highlighted the sarcoprotective role of pyruvate dehydrogenase B (PDHB) ( Jiang et al, 2023 ).…”

Bta-miR-206 and a Novel lncRNA-lncA2B1 Promote Myogenesis of Skeletal Muscle Satellite Cells via Common Binding Protein HNRNPA2B1

“…When exploring the function of genes, the biological function of candidate genes is usually studied by using the expression level of overexpressed or knocked-out candidate genes [ 21 ]. Jiang et al [ 42 ] analyzed the regulatory mechanisms of pyruvate dehydrogenase B (PDHB) on muscle differentiation using primary skeletal muscle cell models in humans and mice, with knockdown or overexpression assays. In this study, MuSCs models were constructed that overexpressed and interfered with lncA2B1; lncA2B1 downregulated the mRNA and protein expression levels of Pax3/Pax7/HDAC4, the number of EdU-positive cells were decreased ( Figure 2 f–h and Figure A1 a,b).…”

Potential impact of cuproptosis-related genes on tumor immunity in esophageal carcinoma

“…Manipulating PDHB expression through knockdown or overexpression resulted in decreased or increased expression of Myf5, MyoD, MyoG, and MyHC, resulting in reduced or increased rates of myogenic differentiation. Additionally, overexpressing PDHB in skeletal muscle alleviated D-galactose-induced sarcopenia in mice [ 28 ].…”