Diosgenin Alleviates Age‐Related Sarcopenia by Promoting Satellite Cell Proliferation and Myogenic Differentiation via Activation of the SIRT1/PGC‐1α Signaling Pathway
It is demonstrated that diosgenin alleviates age‐related sarcopenia by activating the SIRT1/PGC‐1α signaling pathway to promote satellite cell proliferation and myogenic differentiation, highlighting its potential as a promising therapeutic candidate for sarcopenia.
Abstract
Age‐related sarcopenia is characterized by a progressive decline in skeletal muscle mass and function, with satellite cell dysfunction representing a central pathogenic mechanism. Diosgenin, a steroidal saponin derived from plants of the Dioscorea genus, has demonstrated potential anti‐aging properties; however, its role in sarcopenia remains unclear. In this study, naturally aged C57BL/6J mice and a D‐galactose (D‐gal)–induced senescent C2C12 cell model were employed to systematically investigate the effects of diosgenin on muscle function, satellite cell dynamics, and the sirtuin 1 (SIRT1)/peroxisome proliferator‐activated receptor gamma coactivator‐1 alpha (PGC‐1α) signaling pathway. Diosgenin treatment significantly improved forelimb grip strength and exercise endurance, increased the gastrocnemius muscle index, and enlarged muscle fiber cross‐sectional area in aged mice. Mechanistically, diosgenin upregulated the expression of myokines meteorin‐like protein (METRNL) and insulin‐like growth factor 1 (IGF‐1) at both mRNA and protein levels, increased the number of proliferative satellite cells positive for paired box 7 (Pax7) and Ki67, and enhanced the expression of myogenic markers, including myogenic factor 5 (Myf5), Pax7, and myosin heavy chain II (MyHC II). These effects were mediated by direct activation of SIRT1, leading to deacetylation of PGC‐1α. Notably, pharmacological inhibition of SIRT1 with EX527 markedly abrogated the diosgenin‐induced effects. Molecular docking and cellular thermal shift assays further confirmed the direct interaction between diosgenin and SIRT1. Collectively, these findings demonstrate that diosgenin alleviates age‐related sarcopenia by activating the SIRT1/PGC‐1α signaling pathway to promote satellite cell proliferation and myogenic differentiation, highlighting its potential as a promising therapeutic candidate for sarcopenia.
Results showed that FMN improved lean mass, grip strength, mitochondrial membrane potential, and ATP production, while reducing ROS and ferroptosis by regulating ACSL4, GPX4, and SLC7A11.
Xiao Wang, Linhan Zhong, Jun Yang et al.· International Journal of Bio...· 0 citations
Dysregulation of α-KG and L-2HG drives diabetic muscle fibrosis by disrupting TET2-dependent DNA hydroxymethylation and FAP division symmetry, supporting a TET2-dependent mechanism underlying the epigenetic effects of α-KG.
Zhou-Jie Tong, Yihui Li, Ming Song et al.· Metabolism: Clinical and Exp...· 1 citation
Abstract Type 2 diabetes mellitus (T2DM)-associated sarcopenia extends beyond isolated metabolic dysregulation; consequently, standard glucose-centric therapeutic strategies are insufficient to arrest myofibrillar atrophy. In this review, we characterize this pathogenesis through a novel spatial-bioenergetic-immune axis, stratifying disease progression across three hierarchical levels. First, within the tissue niche, the proliferation of CD90⁺ fibro-adipogenic progenitors (FAPs) establishes a pro-inflammatory microenvironment, driving extracellular matrix fibrosis that physically constrains the myogenic niche. Second, at the subcellular organelle level, kinase-driven structural disruption of mitochondria-associated endoplasmic reticulum membranes (MAMs) induces calcium dyshomeostasis and oxidative stress, culminating in bioenergetic collapse and NLRP3 inflammasome assembly. Third, at the immune-nuclear axis, retrograde signaling—exacerbated by GSDMD-mediated sarcolemmal permeabilization—induces sustained transcriptional repression of core myogenic programs. Synthesizing these spatial mechanisms, we propose a comprehensive clinical paradigm. By integrating microenvironmental modulation (SGLT2 inhibitors/GLP-1RAs), structural mechanotransduction (HIIT), and epigenetic rejuvenation (15-PGDH inhibitors), we advocate for a transition toward precision clinical management of T2DM-associated sarcopenia, aimed at arresting skeletal muscle degeneration and preserving physical functional capacity.
Ling-Feng Wu, Hong Ye, Xiao-Feng Wang et al.· Journal of Inflammation Rese...· 0 citations
Intervertebral disc degeneration (IDD) is a leading cause of chronic low back pain, and macrophages play a pivotal regulatory role through metabolic reprogramming that governs M1/M2 polarization. This study aimed to elucidate how the Sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) axis and carnitine palmitoyltransferase 1A (CPT1A)-mediated metabolic reprogramming regulate macrophage polarization in IDD using single-cell RNA sequencing (scRNA-seq), bulk RNA sequencing (bulk RNA-seq), and isotope tracing. A puncture-induced IDD rat model was established. Exploratory scRNA-seq and bulk RNA-seq revealed an increased M1 macrophage trend and identified SIRT1, PGC-1α, and CPT1A as candidate regulators of glycolysis and fatty acid oxidation (FAO). Immunofluorescence, Western blot, and flow cytometry confirmed M1/M2 polarization changes. Lentiviral-mediated overexpression, PGC-1α/CPT1A knockdown rescue, and [¹³C]-glucose and [¹³C]-palmitate isotope tracing demonstrated that activation of the SIRT1/PGC-1α axis and CPT1A enhanced oxidative phosphorylation (OXPHOS) and FAO, reduced glycolytic activity, promoted M2 polarization, suppressed inflammatory cytokines, and mitigated extracellular matrix (ECM) degradation. In vivo administration of the SIRT1 agonist SRT1720 or CPT1A agonist C75 alleviated IDD progression. This study indicates that the SIRT1/PGC-1α/CPT1A axis regulates macrophage polarization through metabolic reprogramming and provides potential therapeutic targets for IDD.
Introduction Empagliflozin is an established sodium-glucose cotransporter 2 inhibitor with reported anti-inflammatory activity, but its effects on advanced glycation end product/high-glucose-induced inflammatory injury in skeletal muscle cells remain unclear. Methods A GEO-derived transcriptomic dataset from gastrocnemius muscle of type 2 diabetes mellitus rats was analyzed to screen pathways associated with diabetes-related skeletal muscle injury, and molecular docking was performed to explore the possible structural compatibility between empagliflozin and RAGE. Differentiated C2C12 myotubes were exposed to AGE-BSA under high-glucose conditions and treated with empagliflozin. Cell viability was assessed using CCK-8, and RAGE, NF-κB, IL-6, and TNF-α were evaluated by qRT-PCR, Western blotting, immunofluorescence, and ELISA. Results Bioinformatic enrichment highlighted AGE-RAGE signaling and inflammation-related NF-κB pathways in diabetic skeletal muscle. Molecular docking provided a computational structural hypothesis suggesting possible compatibility between empagliflozin and human RAGE involving Asp160. In AGE-BSA/high-glucose-stimulated C2C12 myotubes, empagliflozin improved cell viability and was accompanied by reduced RAGE expression, lower NF-κB phosphorylation and immunofluorescence-based nuclear accumulation, and lower IL-6 and TNF-α expression and secretion. Discussion Empagliflozin attenuates AGE-BSA/high-glucose-induced inflammatory injury in C2C12 myotubes, and this effect is associated with reduced activation of RAGE/NF-κB-related inflammatory signaling. Further gain- or loss-of-function experiments and validation in diabetic animal models are required to determine whether this pathway is causally involved and whether the observed cell-based effect can be translated into an in vivo setting.
Xiao-Ying Zhang, Yu Mao, Jiaxing Wu et al.· Frontiers in Endocrinology· 0 citations
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