Increased TWEAK and decreased MyoG expression in age-related impairment of muscle regeneration and H2O2-induced senescence-associated changes in C2C12 cells.
Aug 2026· Experimental Gerontology· pp.
113299
· 0 citations· 31 references
Medicine
TL;DR
It is suggested that TWEAK signaling may be associated with oxidative stress and age-related impairments in muscle regeneration.
Abstract
Sarcopenia is characterized by the progressive loss of skeletal muscle mass and strength, accompanied by impaired regenerative capacity. This study examined age-related changes in skeletal muscle regeneration and the associated expression of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and myogenin (MyoG). Male C57BL/6 mice aged 3, 13, and 23 months were subjected to barium chloride (BaCl2)-induced tibialis anterior muscle injury. In parallel, C2C12 cells were exposed to repeated low-dose hydrogen peroxide (H2O2) to induce senescence-associated changes under oxidative stress, and the effect of the TWEAK inhibitor L524 was evaluated. Muscle mass and grip strength showed age-dependent declines. Following BaCl2 injury, MyoD expression was induced similarly across age groups, whereas MyoG and embryonic myosin heavy chain expression significantly decreased with advancing age. TWEAK expression increased in injured muscle with age, while p-4E-BP1 showed no clear age-dependent change. In C2C12 cells, repeated H2O2 exposure at 100 μM, which maintained cell viability above 90%, induced senescence-associated changes, reduced myotube formation, increased TWEAK expression, and decreased MyoG expression, whereas treatment with the TWEAK inhibitor L524 attenuated the H2O2-associated reduction in MyoG expression. Collectively, these findings suggest that TWEAK signaling may be associated with oxidative stress and age-related impairments in muscle regeneration.
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.
Xin Zeng, Han-Wen Ding, Ziye Li et al.· Aging Cell· 0 citations
INTRODUCTION
Aging is associated with impaired skeletal muscle mass and function, often attributed to reduced sensitivity to anabolic stimuli. This study investigated whether aging influences the sensitivity of key anabolic signaling pathways to mechanical tension development in skeletal muscle.
METHODS
Using an ex vivo model, extensor digitorum longus (EDL) muscles from adult (16 weeks) and old (24 months) female mice were subjected to a standardized passive stretch protocol, with contralateral muscles serving as controls. During recovery, phosphorylation of proteins related to downstream mTORC1 and JNK-SMAD2-L signaling were assessed by immunoblotting.
RESULTS
Passive stretch significantly increased phosphorylation of mTORC1-related proteins (mTOR, p70S6K, rpS6, and 4E-BP1) in both adult and old muscles, with no significant differences between age groups, indicating preserved mTORC1 signaling sensitivity to mechanical tension with aging. In contrast, the magnitude of activation of JNK and SMAD2-L signaling was attenuated in old muscles.
DISCUSSION
Our findings reveal that mechanosensitive anabolic signaling is differentially affected by aging. While the intrinsic capacity for mTORC1 activation in response to mechanical tension appears to be preserved with aging, JNK-SMAD2L signaling exhibits reduced mechanosensitivity in aged muscle. This divergence suggests that aging selectively impairs tension-sensitive transcriptional pathways, potentially constraining muscle remodeling despite preserved translational signaling capacity. These findings further imply that age-related deficits observed in vivo may, at least in part, arise from systemic influences rather than intrinsic defects adhering to mTORC1 mechanotransduction.
J. B. Kristiansen, Jacob Andresen, Jesper Emil Jakobsgaard et al.· Experimental Gerontology· 0 citations
Findings indicate that TWEAK suppression may represent a promising strategy for preserving muscle mass and metabolic homeostasis during aging, though its capacity to fully restore functional capacity requires further investigation.
Zhuoya Maimaitiwusiman, Saiyare Xuekelati, An-Ni Wang et al.· Scientific Reports· 0 citations
Age-related muscle atrophy is closely associated with oxidative stress imbalance. This study investigated the molecular mechanisms by which moderate-intensity aerobic exercise alleviates early oxidative stress and muscle atrophy in senescence-accelerated mouse prone 8 (SAMP8) mice via modulation of the D-amino acid oxidase (DAO)-nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) pathways. 3-month-old male SAMP8 mice and senescence-accelerated mouse resistant 1 (SAMR1) controls were randomised into four groups (n = 10/group): SAMR1-Sed, SAMR1-Ex, SAMP8-Sed, and SAMP8-Ex. The exercise groups performed 12 weeks of moderate-intensity treadmill running. Gastrocnemius muscle morphology was assessed by hematoxylin and eosin (HE), Masson's trichrome, and toluidine blue (TB) staining; oxidative stress markers were measured using biochemical assays; and expression of DAO, serine racemase (SRR), and Nrf2/Keap1 pathway components was quantified by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. Moderate-intensity aerobic exercise significantly increased muscle fibre cross-sectional area, reduced collagen deposition and mast cell degranulation, lowered hydrogen peroxide (H₂O₂), malondialdehyde (MDA), and protein carbonylation levels, and enhanced superoxide dismutase (SOD) activity and glutathione (GSH) content in SAMP8 mice. It downregulated DAO and SRR expression while activating Nrf2, inhibiting Keap1, and upregulating downstream antioxidant genes (Hmox1, Nqo1, Gclc). These findings suggest that moderate-intensity aerobic exercise alleviates early oxidative stress and muscle atrophy by inhibiting the pro-oxidant DAO/SRR pathway and activating the Nrf2/Keap1 antioxidant axis, thereby providing evidence for the molecular mechanisms underlying the attenuation of age-related skeletal muscle degeneration.
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
Klotho is an anti-aging protein involved in phosphate homeostasis, oxidative stress regulation, and tissue regeneration. Although circulating Klotho levels decline with chronological aging, its response to acute disuse- induced skeletal muscle alterations remains unclear. In this experimental study, sixteen male Wistar rats (3 months old) were randomly assigned to a control group (n = 8) or an intermittent hindlimb unloading group (3 h/day for 15 consecutive days) (n = 8). Skeletal muscle morphology was evaluated in the extensor digitorum longus (EDL) and soleus muscles using hematoxylin-eosin staining, and muscle fiber cross-sectional area (CSA) was quantified with ImageJ software. Interstitial connective tissue changes were qualitatively assessed using Masson's trichrome staining, and serum Klotho concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Intermittent unloading induced histological features consistent with early disuse-associated muscle remodeling in both EDL and soleus muscles, accompanied by a modest reduction in muscle fiber CSA compared with controls. Serum Klotho levels were significantly lower in the unloading group (7.44 ± 0.54 vs 8.21 ± 0.81, p = 0.045), and a moderate positive correlation was observed between circulating Klotho concentrations and mean muscle fiber CSA (r = 0.58, p = 0.02). Mild interstitial connective tissue expansion was qualitatively noted in the soleus muscle following unloading. These findings suggest that short-term intermittent hindlimb unloading in young adult rats is associated with reduced circulating Klotho levels and mild skeletal muscle remodeling. Serum Klotho may represent a candidate biomarker of early disuse-associated muscle alterations; however, further studies are required to confirm its clinical applicability. These results may have potential implications for orthopedic conditions characterized by immobilization, including fracture treatment, casting, and postoperative rehabilitation.
S. Key, Ö. Esmez, A. Agar et al.· Acta orthopaedica Belgica· 0 citations
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