Inactivation of SERCA2 at Cys674 induces skeletal muscle atrophy by activating the TGFβ/Smad-S100a4 axis to promote inflammation

KCNE2 upregulation improves cardiac function by inhibiting Smurf1-mediated SERCA2a degradation in diabetic cardiomyopathy in mice.

Aging preserves mTORC1 but attenuates JNK-SMAD2L signaling sensitivity to passive stretch-induced tension development in isolated mouse skeletal muscle.

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.

SERCA2 gatekeeper role in aortic autophagy: targeting the Ca2+-mTOR axis to prevent aortic dissection.

Tectorigenin protects against muscle atrophy from in vitro nutrient deprivation and in vivo denervation by activating the AMPK/SIRT1/PGC-1α pathway.

BACKGROUND AND PURPOSE The molecular mechanisms underlying denervation-induced muscle atrophy remain incompletely understood, and effective therapeutic interventions are currently lacking. Tectorigenin (TG), a natural isoflavonoid, has demonstrated antioxidant and metabolic regulatory activities. This study investigated whether TG also alleviates denervation-induced muscle atrophy via activation of the AMPK/SIRT1/PGC-1α signalling pathway. EXPERIMENTAL APPROACH A sciatic nerve transection model was established in ICR mice to evaluate the therapeutic effects of TG. Histomorphology, oxidative stress markers, mitochondrial function and pathway activity were assessed. A nutrient deprivation-induced C2C12 myotube atrophy model was used for in vitro validation. Pathway-specific inhibitors (Compound C, EX-527 and SR18292) were applied both in vivo and in vitro to confirm mechanistic involvement. KEY RESULTS TG treatment significantly improved muscle wet weight ratio, myofibre cross-sectional area and myosin heavy chain expression in denervated mice. It reduced levels of atrophy-related ubiquitin ligases, attenuated oxidative stress and improved mitochondrial integrity. TG reversed the denervation-induced suppression of AMPK/SIRT1/PGC-1α signalling and downstream effectors. In C2C12 myotubes, TG dose-dependently ameliorated atrophy and up-regulated SIRT1/PGC-1α. Pharmacological inhibition of AMPK, SIRT1 or PGC-1α abolished TG's protective effects, both in vitro and in vivo. CONCLUSIONS AND IMPLICATIONS TG mitigates denervation-induced muscle atrophy through a multi-mechanistic approach involving activation of the AMPK/SIRT1/PGC-1α axis, enhancement of mitochondrial dynamics and restoration of redox homeostasis. This study identifies TG as a promising candidate for clinical translation in the treatment of neurogenic muscle atrophy.

Cryptotaenia japonica extract attenuates glucocorticoid-induced muscle atrophy via regulation of the AKT/mTOR–FOXO/E3 ubiquitin ligase axis

Sarcopenia, characterized by progressive loss of skeletal muscle mass and function, is exacerbated by chronic glucocorticoid exposure, which activates catabolic signaling pathways and accelerates muscle protein degradation. Although Cryptotaenia japonica Hassk (Apiaceae) has been reported to possess antioxidant and anti-inflammatory properties, its role in glucocorticoid-induced muscle atrophy remains unclear. In this study, we investigated the myoprotective effects of Cryptotaenia japonica extract (CJE) using both in vitro and in vivo models. C2C12 myotubes were treated with dexamethasone (Dex, 10 μM) in the presence or absence of CJE (10–100 μg/mL), and key signaling pathways were analyzed by Western blotting and confocal microscopy. In vivo, Dex-induced muscle atrophy was established in ICR mice, followed by oral administration of CJE (200 mg/kg/day). Muscle tissues were evaluated for protein expression, histological alterations, and serum GDF-8 levels. CJE treatment attenuated Dex-induced upregulation of the E3 ubiquitin ligases MuRF-1 and FBX32 and inhibited FOXO1 nuclear translocation in C2C12 myotubes. In dexamethasone-treated mice, CJE restored mTOR phosphorylation and normalized the dexamethasone-induced dysregulation of AKT phosphorylation, while suppressing the FOXO/E3 ubiquitin ligase catabolic axis. In Dex-treated mice, CJE reduced the expression of FOXO3a, MuRF-1, and FBX32, preserved muscle fiber architecture, and increased muscle fiber cross-sectional area. Furthermore, CJE modulated circulating GDF-8 levels associated with muscle atrophy. Collectively, these findings demonstrate that CJE mitigates glucocorticoid-induced muscle atrophy by coordinately regulating the AKT/mTOR–FOXO/E3 ubiquitin ligase signaling axis. These results suggest that CJE may serve as a promising natural therapeutic candidate for the prevention of sarcopenia and muscle-wasting conditions.

iPLA2β: A novel store-operated calcium entry modulator contributing to muscle dysfunction during denervation

iPLA2β deletion normalizes SOCE, preserves Ca2+ homeostasis, and protects against denervation-induced muscle mass and strength loss, revealing that iPLA2β may be a critical link between oxidative stress and Ca2+ dysregulation and a promising target for mitigating muscle dysfunction during denervation.