Aug 2026· Experimental Physiology· 0 citations· 41 references
Medicine
TL;DR
It is indicated that exercise‐induced elevation of body temperature enhances protection against glucocorticoid‐induced skeletal muscle atrophy and support a role for heat‐associated cellular stress responses in modulating muscle protein turnover during glucocorticoid exposure.
Abstract
Abstract Prolonged glucocorticoid exposure induces skeletal muscle atrophy through suppression of protein synthesis and activation of catabolic signalling pathways. Although exercise attenuates glucocorticoid‐induced muscle loss, whether exercise‐induced increases in body temperature contribute remains unclear. In this study, we examined whether exercise in different thermal conditions modulates skeletal muscle atrophy and intracellular signalling during glucocorticoid exposure. Female Sprague–Dawley rats (n = 48) were assigned to six groups: control (CON), dexamethasone‐treated (DEX), cold exercise (∼5°C; CE), cold exercise with dexamethasone (CED), warm exercise (25°C; WE) and warm exercise with dexamethasone. Exercise protocols were matched, and dexamethasone was administered for 5 days. Dexamethasone reduced plantaris muscle mass (by 17%, P < 0.0001) and fibre cross‐sectional area (27%, P < 0.0001). During dexamethasone treatment, exercise in a cold environment provided partial protection, with muscle mass higher than DEX (P = 0.0476), but both muscle mass and fibre CSA remained lower than CON (P = 0.0096 and P = 0.0215, respectively). In contrast, exercise in a warm environment preserved muscle mass and fibre CSA (no difference vs. CON) and resulted in higher muscle mass (P = 0.0070) and fibre CSA (P < 0.0001) than DEX. Exercise‐induced increases in rectal temperature were associated with higher Hsp72 and Hsp25 expression, partial preservation of Akt–FoxO3a signalling and reduced MuRF1 expression, whereas exercise in a cold environment showed minimal heat shock protein response and limited suppression of catabolic signalling. These findings indicate that exercise‐induced elevation of body temperature enhances protection against glucocorticoid‐induced skeletal muscle atrophy and support a role for heat‐associated cellular stress responses in modulating muscle protein turnover during glucocorticoid exposure.
ABSTRACT Aim Repeated heat exposure may promote adaptive remodeling or cumulative tissue burden depending on thermal dose, but its graded molecular and functional consequences during recovery remain unclear. We examined whether repeated moderate (39°C) and severe (41°C) whole‐body hyperthermia produce distinct skeletal muscle trajectories involving mitochondrial dynamics, proteostasis, contractile gene programming, and motor behavior. Methods Adult male Swiss mice underwent 15‐min daily whole‐body heat exposure for 7 days at 39°C or 41°C core temperature and were assessed immediately or after 7 days of recovery. Motor and behavioral outcomes were evaluated using open‐field, elevated plus maze, grip strength, and rotarod tests. Gastrocnemius muscle was analyzed by qRT‐PCR, immunoblotting, and immunofluorescence for mitochondrial biogenesis, dynamics, mitophagy, proteostasis, and contractile phenotype markers. Cerebellar HSP60/HSP70 immunoreactivity and serum corticosterone were also assessed. Results At 39°C, recovery induced coordinated mitochondrial biogenesis and balanced fission‐fusion transcript upregulation. At 41°C, acute Ppargc1a induction (p < 0.01) was followed by recovery‐phase mitophagy and oxidative‐response gene upregulation. Gastrocnemius ERK phosphorylation increased preferentially during 39°C exposure (p < 0.05). HSP60 progressively declined across recovery groups, whereas HSP70 increased only after 41°C recovery (p < 0.05). Grip‐related neuromuscular performance was impaired at 41°C in both phases (p < 0.05), while rotarod performance remained intact. Cerebellar HSP70 was strongly suppressed by heat exposure (p < 0.0001) and partially restored after 39°C recovery. Principal component analysis without group labels reproduced this divergence, yielding a dose × phase interaction axis (p = 5.7 × 10−7). Conclusion Moderate hyperthermia supports adaptive mitochondrial remodeling, whereas severe hyperthermia promotes stress‐related quality control, proteostatic strain, contractile suppression, and reduced grip‐related neuromuscular performance.
Cansu Yakin, C. Erdogan, Fatma Ozge Tuncel et al.· Acta Physiologica· 0 citations
EMS applied during LPS-induced systemic inflammation exacerbated skeletal muscle atrophy and was associated with activation of IL-6/STAT3-C/EBPδ signaling and proteolytic pathways.
Shino Matsukawa, Shinichi Kai, Hideya Seo et al.· Anesthesia and Analgesia· 0 citations
Fibroblast growth factor 21 (FGF21) regulates lipid metabolism, and lactate may act centrally to modulate energy homeostasis. This study examined whether central FGF21 contributes to exercise-induced fat oxidation and whether central lactate regulates its induction and sympathetic-driven lipolysis. Male Wistar rats received intracerebroventricular (ICV) administration of FGF21 or lactate, or performed acute endurance exercise under three conditions: standard exercise, exercise with inhibited brain lactate transport using α-cyano-4-hydroxycinnamate (4-CIN), or exercise with reduced systemic lactate production via dichloroacetate (DCA). Cerebrospinal fluid (CSF) FGF21, central FGF21 expression, and peripheral fat oxidation indices were measured. Exercise selectively increased hypothalamic FGF21 mRNA and protein, and CSF FGF21 (all p < 0.01), without affecting cortex or hippocampus. This was accompanied by activation of p38 mitogen-activated protein kinase (p38-MAPK) and extracellular signal-regulated kinase 1/2 (ERK1/2), elevated plasma catecholamines, increased adipose cyclic adenosine monophosphate (cAMP), and enhanced hormone-sensitive lipase (HSL) phosphorylation, indicating sympathetic-driven lipolysis. ICV lactate at rest reproduced these effects via G protein-coupled receptor 81 (GPR81)-p38-MAPK signaling, whereas inhibition of p38-MAPK or GPR81 abolished lactate-induced FGF21 expression. ICV FGF21 increased catecholamines, adipose cAMP, and HSL phosphorylation, effects blocked by the FGF21 receptor antagonist BGJ-398. Inhibiting brain lactate uptake before exercise attenuated hypothalamic FGF21 induction, sympathetic activation, and fat mobilization, whereas systemic lactate reduction had a weaker effect, suggesting that brain lactate uptake contributes importantly to exercise-induced hypothalamic FGF21 regulation and fat mobilization. Taken together, these findings support a role for central lactate uptake in the activation of hypothalamic GPR81-p38-MAPK-FGF21 signaling and suggest that this pathway contributes to exercise-induced sympathetic activation and fat mobilization.
Fateme Mansouri, R. Nikooie, Mohammad Mehrtash et al.· Molecular and Cellular Endoc...· 0 citations
ABSTRACT It remains unclear why exercising damaged muscles is perceived as disproportionately more effortful. Given the known role of inorganic phosphate (Pi) in fatigue and afferent sensory signaling, we tested whether muscle damage disrupts phosphate metabolism and whether this is associated with heightened ratings of perceived exertion (RPE). Eighteen adults (23 ± 4 years) completed assessments before and 48 h after muscle damage induced by unilateral eccentric knee extensions (EIMD); the contralateral leg served as control. Magnetic resonance imaging quantified quadriceps cross‐sectional area (Qcsa) and 31P‐MR spectroscopy quantified Pi, phosphocreatine (PCr), Pi/PCr, ATPγ and pH at rest, during knee‐extension exercise, and recovery. RPE was recorded throughout exercise. At 48 h, the EIMD leg showed increased soreness (17‐fold), reduced maximum voluntary contraction (−18.4% ± 3.8%) and increased Qcsa (+2.8% ± 0.4%; mean individual percentage changes ± SEM; p < 0.001). Visit × condition interactions were observed for Pi, Pi/PCr, and ATPγ at rest (ηp2 = 0.31–0.35) and across rest, exercise and recovery (ηp2 = 0.66–0.78), but not for PCr or pH. This reflected sustained elevations of Pi and Pi/PCr, and lower ATPγ in the EIMD leg alongside higher RPE at 48 h. Elevated resting Pi/PCr was strongly associated with elevated RPE (r = 0.856, p < 0.001), whereas exercise‐induced Pi/PCr changes were not associated with RPE. Overall, EIMD causes a sustained disturbance in muscle phosphate homeostasis that is strongly associated with elevated RPE. These findings provide new evidence linking resting muscle phosphate‐metabolic disturbance with heightened effort perception after damage.
Jamie S McPhee, Aneurin J Kennerley, Jean‐Christophe Lagacé et al.· Scandinavian Journal of Medi...· 0 citations
Background/Objectives: Alternate-day fasting (ADF) combined with exercise has been suggested as an effective lifestyle strategy for reducing fat mass while preserving lean mass. However, whether exercise preconditioning before ADF plus concurrent exercise affects subsequent body-composition and substrate-utilization responses remains unclear. This study aimed to evaluate the effects of exercise preconditioning during a subsequent ADF plus concurrent exercise intervention. Methods: Seven-week-old male ICR mice were assigned to the non-exercise preconditioning (Non-ExPC) or exercise preconditioning (ExPC) group (n = 8/group). After the 4-week preconditioning period, both groups underwent 7 days of ADF plus concurrent exercise. Resting energy metabolism was measured during the intervention, and body composition, exercise energy metabolism, muscle and motor function, blood biomarker concentrations, and plasma hormone levels were assessed before and after the intervention. Results: Both groups showed significant reductions in body weight, body fat percentage, and fat mass after the intervention. Lean mass decreased in both groups without between-group differences. The ExPC group maintained significantly lower body fat percentage and fat mass than the Non-ExPC group and showed significantly higher resting oxygen uptake, carbon dioxide production, respiratory exchange ratio, carbohydrate oxidation, and energy expenditure during the intervention. During exercise, the respiratory exchange ratio and carbohydrate oxidation significantly increased in both groups, whereas fat oxidation significantly decreased only in the ExPC group. Conclusions: Exercise preconditioning was associated with the maintenance of lower adiposity during short-term ADF combined with concurrent exercise, while differences in substrate utilization were observed under some conditions.
Jungyong Lee, Taeho Kim, Deunsol Hwang et al.· Metabolites· 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