Jul 2026· Journal of Cachexia, Sarcopenia and Muscle· Vol 17· 0 citations· 40 references
Medicine
TL;DR
Findings indicate that pharmacological regulation of mitochondrial stress responses influences skeletal muscle vulnerability under chronic metabolic stress and identify skeletal muscle as a previously underappreciated target of imeglimin action.
Abstract
ABSTRACT Background Sarcopenia is a major contributor to frailty and mortality in ageing and obesity and is tightly linked to metabolic dysfunction. Imeglimin is a first‐in‐class oral hypoglycaemic agent targeting mitochondrial function; however, despite the central role of mitochondria in skeletal muscle homeostasis, its effects on skeletal muscle under sarcopenia‐relevant conditions remain unclear. Methods Imeglimin was administered to male C57BL/6 mice with high‐fat diet (HFD)–induced obesity for 6 weeks and to naturally aged (18 months old) male mice for 12 weeks. Skeletal muscle fibre morphology and transcriptomic profiles were analysed in fast‐ and slow‐twitch muscles. In parallel, C2C12 myotubes were exposed to palmitate with or without imeglimin, and inflammatory gene expression and reactive oxygen species (ROS) generation were assessed. Results Imeglimin significantly increased the cross‐sectional area (CSA) of Type II fibres in the extensor digitorum longus (EDL) muscle of HFD‐fed mice (+66%, p < 0.01 vs. controls). Transcriptomic analyses revealed suppression of conserved molecular signatures of muscle atrophy, including activation of immediate‐early genes and inflammatory pathways (−62% to −79%, p < 0.05 vs. HFD‐fed mice). In palmitate‐treated C2C12 myotubes, imeglimin attenuated lipotoxicity‐induced inflammatory gene expression (−28% to −72%, p < 0.05 vs. controls) with reduced ROS generation, consistent with its cell‐autonomous effect on myocytes. Notably, in naturally aged mice, 12‐week imeglimin treatment preserved EDL muscle fibre size (+14%, p < 0.05 vs. controls) without altering systemic glucose tolerance, accompanied by transcriptomic changes overlapping with those observed in the HFD model (−27% to −82%, p < 0.05 vs. aged controls). Conclusions Imeglimin attenuates skeletal muscle atrophy in obesity and ageing, accompanied by coordinated suppression of stress‐ and inflammation‐associated transcriptional programmes. These findings indicate that pharmacological regulation of mitochondrial stress responses influences skeletal muscle vulnerability under chronic metabolic stress and identify skeletal muscle as a previously underappreciated target of imeglimin action.
ABSTRACT Background Skeletal muscle atrophy in amyotrophic lateral sclerosis (ALS) drives loss of muscle strength, function and quality of life in ALS patients. The endocannabinoid system (ECS) regulates muscle homeostasis via regenerative and metabolic processes, and although ECS alterations have been reported in ALS neural tissues, ECS remodelling within ALS skeletal muscle has never been studied. This study investigated temporal and muscle type–specific ECS changes in ALS. Methods Female hSOD1G93A transgenic mice and nontransgenic littermates were studied at presymptomatic and symptomatic ages (56–138 days of age; n = 7–8/group). Endocannabinoids, N‐acyl‐ethanolamine congeners and inflammatory lipid mediators were quantified using targeted LC–MS/MS in the tibialis anterior (TA) and soleus (SOL) muscles. ECS‐related enzymes and receptors were assessed by immunoblotting and integrated with transcriptomic analyses of skeletal muscle biopsies from ALS patients (n = 5/group; ~63 years). To evaluate therapeutic relevance, ALS mice were treated with the fatty acid amide hydrolase (FAAH) inhibitor URB937 or vehicle (n = 10–11/group), and survival, body weight, welfare and motor function were assessed longitudinally. Results ALS caused severe atrophy in the predominantly fast‐twitch TA muscle (−76.5%; p < 0.01), while the slow‐twitch soleus was largely preserved (−14.4%; p < 0.01). Accordingly, the lipid perturbation due to ALS was more pronounced in the TA, reflected by extensive alterations in unsaturated fatty acids, hydroxy‐ and epoxy‐fatty acids (TA: 63% and SOL: 22% of lipid mediators different between ALS vs. NTG) and marked ECS remodelling, including elevated anandamide (+37.3%; p = 0.03) and multiple N‐acyl‐ethanolamine congeners (+76–102%; p < 0.05), reduced 2‐arachidonoylglycerol (−28%; p = 0.06), increased CB1 receptor expression (+93%; p < 0.01) and dynamic, age‐dependent regulation of FAAH (presymptomatic: −68%; p = 0.04, symptomatic: +21%; p = 0.02). In contrast, the SOL showed modest or opposite changes, consistent with its relative resistance to atrophy. Notably, ECS remodelling in the TA was already evident at presymptomatic age (e.g., CB1: +76%; p = 0.01) and the same ECS enzymes were affected in human ALS skeletal muscle transcriptomes (e.g., twofold decrease in FAAH; p FDR = 0.010). Despite evidence for a therapeutic potential, chronic peripheral FAAH inhibition with URB937 did not improve weight loss, motor functions and survival of ALS mice (all p > 0.05). Conclusions Muscle type–specific endocannabinoid system remodelling in ALS precedes overt neurological decline and might relate to degenerative features such as metabolic disturbance and inflammation. Although peripheral FAAH inhibition alone was insufficient to modify disease outcomes, these findings identify the endocannabinoid system as an integral component of ALS muscle pathology and support skeletal muscle lipid signalling as a potentially relevant early target for adjunctive therapeutic strategies.
Sebastiaan Dalle, Kaat Vanderbeke, T. Burg et al.· Journal of Cachexia, Sarcope...· 0 citations
Obesity develops through progressive metabolic alterations that arise long before overt disease, highlighting the need for pharmacological strategies capable of targeting the earliest tissue adaptations to fat nutrient excess. Skeletal muscle plays a central role in systemic metabolic homeostasis and is among the first organs affected by high-fat diet (HFD) exposure. Oleoylethanolamide (OEA), a peroxisome proliferator-activated receptor alpha (PPAR-α) agonist, exerts broad metabolic actions in obesity, yet its impact on early skeletal muscle remodeling remains unknown. We investigated whether OEA could intercept the initial metabolic adaptations induced by HFD exposure in young rats. Male rats were exposed to HFD for seven weeks and treated with OEA (10mg/kg, i.p.) during the final two weeks. Short-term HFD induced a coordinated remodeling of skeletal muscle characterized by lipid accumulation, suppression of the PPAR-α/CPT-1 axis, altered mitochondrial and redox homeostasis, extracellular matrix remodeling, impaired myogenic signaling, and a shift toward a glycolytic contractile program despite only modest body-weight gain. OEA largely attenuated such alterations, preserving skeletal muscle metabolic and structural homeostasis through coordinated improvement of lipid oxidative metabolism, mitochondrial energetic status, and tissue remodeling. These findings identify skeletal muscle as an early target of fat-induced metabolic dysfunction and support further investigation of OEA as a promising pharmacological strategy to intercept obesity-associated metabolic deterioration before overt obesity develops.
M. Friuli, B. Eramo, Nisha Zahid et al.· Pharmacological Research· 0 citations
Sarcopenia is characterized by progressive loss of skeletal muscle mass and function and is increasingly recognized to be influenced by metabolic disturbances associated with aging and obesity. Intramuscular lipid accumulation has emerged as a key pathological feature linking metabolic dysfunction to skeletal muscle deterioration. Celery seed extract (CSE) possesses anti-obesity, anti-inflammatory, and antioxidant properties; however, its potential role in skeletal muscle metabolism has not been well investigated. This study aimed to determine whether CSE attenuates skeletal muscle deterioration associated with obesity and aging through modulation of intramuscular lipid accumulation and related metabolic pathways.
Diet-induced obese mice and naturally aged mice were used to evaluate the effects of CSE supplementation. Skeletal muscle mass, grip strength, muscle morphology, intramuscular lipid content, mitochondrial metabolic signaling, inflammatory responses, and muscle protein turnover pathways were assessed using biochemical, molecular, and histological analyses.
CSE supplementation significantly improved skeletal muscle mass, grip strength, and muscle fiber cross-sectional area in both obese and aged mice. These improvements were accompanied by reduced intramuscular triglyceride and cholesterol accumulation. Mechanistically, CSE improved mitochondrial metabolic signaling by activating the AMPK–PGC-1α pathway and increasing mitochondrial oxidative phosphorylation proteins. In addition, CSE suppressed inflammatory signaling pathways, including MAPK activation and NLRP3 inflammasome signaling, and improved muscle proteostasis by enhancing myogenic regulators while reducing the expression of proteolytic factors such as MuRF1, Atrogin-1, and myostatin. Correlation analyses further indicated that intramuscular lipid accumulation was closely associated with mitochondrial dysfunction, inflammatory activation, and muscle atrophy.
These findings demonstrate that CSE alleviates skeletal muscle deterioration in both obesity- and aging-associated sarcopenia by reducing intramuscular lipid accumulation and improving mitochondrial metabolism, inflammatory responses, and muscle protein turnover. Targeting intramuscular lipid accumulation may therefore represent a promising nutritional strategy for preventing sarcopenia associated with metabolic and aging-related stress.
Su-Kyung Shin, Jiwon Jeong, Min-Jeong Kim et al.· Frontiers in Nutrition· 0 citations
Meloxicam (Mcam) is identified as a small molecule inducer of Cdon that enhances myogenic differentiation, increases muscle mass and function in young mice and mitigates age-related muscle atrophy, and is identified as a potential therapeutic target for age-associated skeletal muscle degeneration.
Ju-Hyeon Bae, Hyun-Kyung So, Yideul Jeong et al.· Experimental and Molecular M...· 0 citations
OBJECTIVE
The present study investigated the role of Drp1 in cuproptosis and its underlying mechanisms, while examining the effects of aerobic exercise on high-fat diet-induced skeletal muscle atrophy. These findings may provide a theoretical basis for exercise interventions and targeted therapies for obesity-associated skeletal muscle atrophy.
METHODS
Five-week-old male C57BL/6 J mice (n = 10 per group) were randomly assigned to a normal diet (ND) or high-fat diet (HFD) and subsequently subjected to aerobic exercise or Mdivi-1 intervention for 8 weeks. Body composition, skeletal muscle mass, grip strength, and endurance capacity were evaluated. Muscle morphology, mitochondrial function, oxidative stress, and copper homeostasis were assessed using H&E staining, JC-1 staining, DHE staining, biochemical assays, and copper measurements. Muscle atrophy proteins, Drp1, and cuproptosis markers were assessed at protein and mRNA levels by Western blotting, immunofluorescence, and RT-qPCR. Differences among multiple groups were analyzed using two-way ANOVA, whereas differences between two groups were analyzed using Student's unpaired t-test.
RESULTS
HFD induced skeletal muscle atrophy, as evidenced by reduced muscle mass, grip strength, and endurance capacity. This was accompanied by mitochondrial dysfunction, oxidative stress, and increased expression of Drp1 and cuproptosis-related markers. Aerobic exercise significantly ameliorated these pathological changes. Similar protective effects were observed following pharmacological inhibition of Drp1 with Mdivi-1.
CONCLUSIONS
Aerobic exercise alleviates HFD-induced skeletal muscle atrophy by suppressing Drp1 expression, thereby reducing copper accumulation and cuproptosis in skeletal muscle.
Min Hu, Yiwen Yuan, Zhenxian An et al.· Cellular Signalling· 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
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