Denervation Research Articles

Purpose The purpose of this study is to improve understanding of which perioperative variables may influence outcomes and return to activity after arthroscopic debridement of patellar tendinopathy. Methods A keyword search was performed in the PubMed, Embase, CINAHL, Scopus, and Cochrane databases for prospective articles published from 2000 to March, 2024 that studied arthroscopic intervention for refractory patellar tendinopathy. 1885 articles were screened using PRISMA guidelines. Outcomes included subjective Success, Return to Sport (RTS) and patient reported outcomes measures (PROMs). Variables included operative techniques of patellar bony work (PBW), Hoffa’s fat pad debridement (HFPD), peripatellar denervation (DNRV), pre-operative duration of symptoms (DOS), and post-operative immobilization (POI). Data were analyzed descriptively and plotted with I2 and 95% confidence intervals where appropriate. Results Eight prospective arthroscopic studies with a total of 260 patients were included in analysis, with mean follow-up 45.2 months (range 6-79). Average success and RTS rates were 90.2% (range 80-100%) and 90.6% (range 85.7-100%), respectively. There was a weak negative correlation between subjective success rate and DOS (R2=0.14). Studies reported RTS times ranging from 2.2 months to 4.96 months from the day of surgery. Conclusions For refractory patellar tendinopathy, arthroscopic debridement of the patellar tendon is a safe and effective procedure that allows rapid return to sport. Surgeons may elect to forgo patellar bony work and Hoffa’s fat pad debridement in favor of a conservative approach for athletes seeking to return to sport quickly. However, these decisions should always be considered in the circumstances of the individual patient and intraoperative findings.

Volatile anesthetics are gaining attention as sedatives in intensive care units. Sedation is a significant risk factor for skeletal muscle atrophy and weakness in critically ill patients; however, volatile anesthetics' influence on skeletal muscle atrophy remains unclear. Therefore, we investigated their effects on skeletal muscle mass using a murine-derived muscle cell line and mice. C2C12 myotubes were exposed to isoflurane or sevoflurane. Myotube diameter was assessed using immunofluorescence. The expression levels of Atrogin-1, MuRF1, and LC3-II and phosphorylation levels of p70 S6K and Akt were analyzed to evaluate protein degradation and synthesis. To determine whether these effects were mediated through the Akt pathway, experiments with insulin-like growth factor 1 (IGF-1) were performed. Furthermore, mice skeletal muscle exposed to isoflurane or sevoflurane were compared with control mice and short-term immobility mice induced by sciatic nerve denervation (DN) or hindlimb suspension (HS). Exposure of C2C12 myotubes to 2.8% isoflurane or 5.0% sevoflurane reduced the myotube diameter by 14.4 µm (95% confidential interval [CI], 11.7-17.1, P < .001) and 13.2 µm (95% CI, 10.1-16.2, P < .001), respectively. Exposure to 2.8% isoflurane increased the expressions of Atrogin-1 (2.9-fold [95% CI, 2.1- to 3.8-fold], P < .001), MuRF1 (3.1-fold [95% CI, 2.4- to 3.8-fold], P < .001), and LC3-II (1.6-fold [95% CI, 1.4- to 1.8-fold], P < .001), whereas decreasing phosphorylation of p70 S6K (0.3-fold [95% CI, 0.2- to 0.4-fold], P < .001) and Akt (0.4-fold [95% CI, 0.3- to 0.5-fold], P < .001). Exposure to 5.0% sevoflurane resulted in similar effects. Additionally, IGF-1 counteracted the effects of isoflurane on myotube mass. In mice skeletal muscle, exposure to 1% isoflurane or 1.5% sevoflurane decreased Akt phosphorylation (isoflurane: 0.4-fold [95% CI, 0.1- to 0.8-fold], P = .003; sevoflurane: 0.5-fold [95% CI, 0.4- to 0.6-fold], P = .011) and increased the expression levels of Atrogin-1 (isoflurane: 4.1-fold [95% CI, 3.2- to 5.1-fold], P < .001; sevoflurane: 2.3-fold [95% CI, 1.1- to 3.5-fold], P = .026), MuRF1 (isoflurane: 2.7-fold [95% CI, 1.3- to 4.1-fold], P = .01; sevoflurane: 2.3-fold [95% CI, 1.0- to 3.7-fold], P = .022), and LC3-II (isoflurane: 1.9-fold [95% CI, 0.9- to 3.0-fold], P = .045; sevoflurane: 1.5-fold [95% CI, 1.4- to 1.6-fold], P < .001) while decreasing p70 S6K phosphorylation (isoflurane: 0.5-fold [95% CI, 0.4- to 0.6-fold], P = .013; sevoflurane: 0.7-fold [95% CI, 0.6- to 0.8-fold], P = .008) compared with DN. Similar results were observed when comparing between isoflurane or sevoflurane exposure and HS. Volatile anesthetics induce skeletal muscle atrophy by downregulating the Akt pathway, suggesting they may exacerbate skeletal muscle atrophy beyond immobility effects.

Belt electrode skeletal muscle stimulation (B-SES) is a method of applying electricity to contract muscles using belt-shaped electrodes. We previously reported that twitch contractions increase mitochondrial synthesis and suppress muscle proteolysis. In contrast, tetanus contraction increases muscle protein synthesis and suppresses muscle proteolysis. This study aimed to determine whether combining twitch- and tetanus-mode stimulations, which are known to differentially regulate mitochondrial and protein synthesis pathways, can more effectively attenuate muscle atrophy induced by denervation. Male Sprague-Dawley rats were subjected to acute or chronic B-SES. In the acute study, animals were assigned to control (CONT), tetanus (60 Hz), or Combined Stimulation (CS: 7-8 Hz for 15 min to 60 Hz for 3 min) groups. Four groups were tested in the chronic study: CONT, denervation (DEN), DEN + 60 Hz, and DEN + CS groups. Acute stimulation resulted in significantly lower muscle glycogen level, increased phosphorylated AMPK and p70S6K in the gastrocnemius muscle (GAS、n = 4) at 60 and CS compared to CONT, with no difference between 60 and CONT. After seven days, both muscle wet weight and cross-sectional area (CSA) were significantly reduced in the DEN group. Although both 60 Hz and CS attenuated atrophy, CS resulted in greater preservation (GAS CSA: DEN + CS, 71% CONT; DEN + 60, 61% CONT). In conclusion, the combination of different stimulation modalities (frequencies) was more effective than continuous tetanus stimulation in preventing denervation-induced muscle atrophy owing to an increase in muscle protein synthesis and inhibition of mitochondrial reduction.

Skeletal muscle atrophy is frequently caused by the disuse of muscles.It impacts quality of life, especially in aging populations and those with chronic diseases. Understanding the molecular mechanisms underlying muscle atrophy is crucial for developing effective therapies. To investigate the roles of vascular endothelial growth factor (VEGF) and various microRNAs (miRNAs) in muscle atrophy using a mouse model of denervation (DEN)-induced disuse, and to elucidate their interactions and regulatory functions through comprehensive network analysis. The right sciatic nerve of C57BL/6J mice (n=6) was excised to simulate DEN, with the left serving as a sham surgery control (Sham). Following a two-week period, wet muscle weight was measured. Total RNA was extracted from the tibialis anterior muscle for microarray analysis. Significant expression changes were analyzed via Kyoto Encyclopedia of Genes and Genomes (KEGG)pathway analysis and miRNet for miRNAs. Denervated limbs showed a significant reduction in muscle weight. Over 1,000 genes displayed increased expression, while 527 showed reductions to less than half of control levels. VEGF, along with specific miRNAs such as miR-106a-5p, miR-mir20a-5p, mir93-5p and mir17-5p, occupied central regulatory nodes within the gene network. Functional analysis revealed that these molecules are involved in key biological processes including regulation of cell migration, vasculature development, and regulation of endothelial cell proliferation. The increased miRNAswere subjected to further network analysis that revealed significant regulatory interactions with target mRNAs. VEGF and miRNAs play crucial roles in the progression of skeletal muscle atrophy, offering potential targets for therapeutic interventions aimed at reducing atrophy and enhancing muscle regeneration.

Skeletal muscle atrophy is a known risk factor for immunosuppressive conditions and for a poor prognosis in sepsis. However, its immunopathology has not been experimentally elucidated. This study investigated the effects of skeletal muscle atrophy on the immunopathology of sepsis. Male C57BL/6J mice were subjected to sciatic denervation (DN) and caecal ligation and puncture (CLP) to induce muscle atrophy or sepsis. The macrophages, myeloid-derived suppressor cells (MDSC), and T-cells in peritoneal and spleen were analysed using flow cytometry. DN-induced muscle atrophy did not affect macrophage and MDSC populations. In contrast, the percentage of cytotoxic T-lymphocyte-associated antigen (CTLA)-4+ CD4+ T-cells, programmed death (PD)-1+ CD8+ T-cells, regulatory T-cells, and the CTLA-4+ regulatory T-cells was statistically significantly higher in DN-CLP mice than in sham-CLP mice. Skeletal muscle atrophy before sepsis triggers excessive Tcell immunosuppression, which may contribute to the exacerbation of sepsis under skeletal muscle atrophy.

Objective: Endovascular renal denervation (DRN) is a therapeutic approach for resistant arterial hypertension (RH). The aim of this study was to assess the effects of RDN on 24h blood pressure. Design and method: A retrospective evaluation of ABPM data at baseline and after 6 months from RDN in patients undergoing DRN between 01/01/2011 and 31/12/2021 in the Arterial Hypertension Center of Turin. Mean 24h, Daytime, Nighttime BP and HR values and short term 24h, daytime and nigthtime BP and HR varability parameters (standard deviation, dipping and coefficient of variation) were calculated. Results: The series included 14 subjects, of which 8 (57%) were female and with an average age 54±10 years. The number of antihypertensive drugs before renal denervation was 5.7±1.0. At baseline office BP was 188/113±22±18 mmHg and ABPM 24h BP was 150/92±21±16 mmHg. Patients were considered as responders if a reduction of least 10 mmHg in systolic blood pressure (PAS) at 24h Blood Pressure Monitoring at six months from RDN was obtained. From a safety point of view, there were no short-term or long-term complications. The responders at six months were 66%. Non-responders showed an increased blood pressure variability compared to responders at baseline and only one was dipper. The responders had a statistically significant redution of SD24h after DRN, an increased average nocturnal blood pressure drop and a lower pressure variability. While in non-responders no redution in SDnight, SDday and coefficient of variation was found, by contrast all of them become dippers because mean daytime SBP increase. Conclusions: In conclusion, pressure variability (SD24h and coefficient of variation) is globally reduced in the denerved patients, this trend is particularly present in responders. The non-responders have an increased BP variability at baseline without decreasing after DRN. These results suggest that, when effective, DRN can reduce both BP levels and BP variability, thus may have an important effect in reducing cardiovascular risk.

Coactivator-associated arginine methyltransferase 1 (CARM1) catalyzes the methylation of arginine residues on target proteins critical for health and disease. The purpose of this study was to characterize the effects of short-term, pharmacological CARM1 inhibition on skeletal muscle size, function, and atrophy. Adult mice (n = 10 or 11/sex) were treated with either a CARM1 inhibitor (150 mg/kg EZM2302; EZM) or vehicle (Veh) via oral gavage for 11-13 days and muscle mass, function, and exercise capacity were assessed. In addition, we investigated the effect of CARM1 suppression on unilateral hindlimb denervation (DEN)-induced muscle atrophy (n = 8/sex). We report that CARM1 inhibition caused significant reductions in the asymmetric dimethylation of known CARM1 substrates but no change in CARM1 protein or mRNA content in skeletal muscle. Reduced CARM1 activity did not affect body or muscle mass, however, we observed a decrease in exercise capacity and muscular endurance in male mice. CARM1 methyltransferase activity increased in the muscle of Veh-treated mice following 7 days of DEN, and this response was blunted in EZM-dosed mice. Skeletal muscle mass and myofiber cross-sectional area were significantly reduced in DEN compared with contralateral, non-DEN limbs to a similar degree in both treatment groups. Furthermore, skeletal muscle atrophy and autophagy gene expression programs were elevated in response to DEN independent of CARM1 suppression. Collectively, these results suggest that short-term, pharmacological CARM1 inhibition in adult animals affects muscle performance in a sex-specific manner but does not impact the maintenance and remodeling of skeletal muscle mass during conditions of neurogenic muscle atrophy.NEW & NOTEWORTHY Short-term pharmacological inhibition of coactivator-associated arginine methyltransferase 1 (CARM1) was effective at significantly reducing CARM1 methyltransferase function in skeletal muscle. CARM1 inhibition did not impact muscle mass, but exercise capacity was impaired, particularly in male mice, whereas morphological and molecular signatures of denervation-induced muscle atrophy were largely maintained in animals administered the inhibitor. Altogether, the role of CARM1 in neuromuscular biology remains complex and requires further investigation of its therapeutic potential in muscle-wasting conditions.

Objective: Renal denervation (DRN) is one of the invasive therapeutic approaches of resistant arterial hypertension. The aim of this study was to re-evaluate patients undergoing DRN, in terms of safety and efficacy. Design and method: A retrospective evaluation of patients undergoing DRN between 01/01/2011 and 31/12/2021 in the Arterial Hypertension Center of Turin. Results: The series included 14 subjects, of which 8 (57%) were female and with an average age 54±10 years. The number of antihypertensive drugs before renal denervation was 5.7±1.0 and at baseline the blood pressure was 188/113±22±18 mmHg. 28% of subjects had a history of ischemic heart disease and 27% of previous stroke and/or transient ischemic event. 9 subjects were denervated with Symplicity device, 1 with Vessix, 4 with Symplicity Spyral. The mean duration of follow-up was 5.2 years. From a safety point of view, there were no short-term or long-term complications. In terms of efficacy, the number of responders at 6 months, defined as a reduction of at least 10 mmHg in systolic blood pressure (PAS) at 24h Blood Pressure Monitoring, was 9 subjects (64%). Two subjects reported systolic blood pressure values below 135 mmHg. Regarding the type of device used, 75% of subjects treated with Spiral devices were responders, compared with 60% of subjects treated with other catheters. Among the non-responders, 2 presented events one year after the DRN. Only 1 responder had high level of renin at baseline. Conclusions: The data relating to the case studies of the Arterial Hypertension Center of Turin highlight the safety of the renal denervation procedure and a blood pressure response in 60% of patients. The latest generation catheters seems to be more effective. However, the small number of cases did not allow to identify predictive factors of response to DRN.

Background: Patients with underlying skeletal muscle atrophy are likely to develop aggravated sepsis. However, no study has experimentally verified the association between the prognosis of sepsis and muscle atrophy, and the mechanism of aggravation of sepsis under muscle atrophy remains unclear. In this study, we investigated the effect of skeletal muscle atrophy induced by sciatic denervation (DN), an experimental muscle atrophy model, on sepsis prognosis. Methods: Skeletal muscle atrophy was induced by DN of the sciatic nerve in C57BL/6J male mice. Cecal ligation and puncture (CLP) was performed to induce sepsis. Results: The survival rates of the sham and DN groups 7 days after CLP were 63% and 35%, respectively, wherein an approximately 30% reduction was observed in the DN group ( P < 0.05, vs. sham-CLP). The DN group had a higher bacterial count in the blood 48 h after CLP ( P < 0.05, vs. sham-CLP). Notably, NOx (a metabolite of nitric oxide) concentrations in DN mice were higher than those in sham mice after CLP ( P < 0.05, vs. sham-CLP), whereas serum platelet levels were lower 48 h after CLP ( P < 0.05, vs. sham-CLP). In organ damage analysis, DN mice presented increased protein expression of the kidney injury molecule (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL), a kidney injury marker, after CLP (NGAL 48 h after CLP, P < 0.05, vs. sham-CLP; KIM-1 24 h after CLP, P < 0.01, vs. sham-CLP). Furthermore, nitro tyrosine levels in the kidneys of DN mice were higher 48 h after CLP compared with those in sham-CLP mice, indicating the accumulation of nitrative stress ( P < 0.05, vs. sham-CLP). Serum cytokine levels were increased in both groups after CLP, but decreased in the sham group 48 h after CLP and remained consistently higher in the DN group (tumor necrosis factor [TNF]-α: P < 0.05, sham-CLP vs. DN-CLP; interleukin (IL)-1β: P < 0.01, sham-CLP vs. DN-CLP; IL-6: P < 0.05, DN vs. DN-CLP; IL-10: P < 0.05, sham-CLP vs. DN-CLP). Conclusions: We verified that skeletal muscle atrophy induced by DN is associated with poor prognosis after CLP-induced sepsis. Importantly, mice with skeletal muscle atrophy presented worsening sepsis prognosis at late onset, including prolonged infection, persistent inflammation, and kidney damage accumulation, resulting in delayed recovery.

Метою дослідження є визначення координат вимірів на підставі магнітно-резонансної томографії з метою удосконалення ендоскопічного доступу для денервації поперекових дуговідросткових суглобів. Матеріал і методи. Проаналізовано магнітно-резонансні томограми (потужність магнітного поля в 1,5 та 3,0 тесли) у 13 пацієнтів (5 чоловіків та 8 жінок віком від 29 до 78 років, середній вік — 57,8 року) з остеохондрозом та клінічно значущим синдромом спондилоартралгії поперекового відділу хребта. Дослідження проводилось у режимах Т1, Т2, Т2fs (жиропригнічення). Виміри для планування доступу здійснювали за допомогою програми RadiAnt DICOM Viewer 1.9.16. Результати дослідження. У міжфасціальних просторах для виконання малоінвазивного доступу в режимах Т1, Т2 та Т2fs кут нахилу тубусу ендоскопа в аксіальній проекції становив від 69,4 до 84,3°, а в сагітальній — від 9,2 до 15,7°. Відступ від верхнього краю остистого відростка в поперечному напрямку становив від 36 до 57 мм. У 3 пацієнтів (23 %) в аксіальних та коронарних проекціях на рівні сегментів L4–L5 та L5–S1 медіальні гілочки візуалізувались у місці їх відходження від спинномозкових нервів, а в 10 пацієнтів (77 %) візуалізація чітко не визначалася. Висновки. Визначення координат за даними магнітно-резонансної томографії за допомогою програми RadiAnt DICOM Viewer 1.9.16 на кісткових орієнтирах суттєво зменшує час на виділення нервів та запобігає додатковому травмуванню підлеглих м’яких тканин, а як метод нейровізуалізації на певних зрізах в аксіальній Т2 та коронарній Т2fs проекціях допомогає візуалізувати медіальні гілочкі задніх гілок спинномозкових нервів у 23 % випадків.

22. LARGE-SCALE, MULTI-ETHNIC RESOURCE OF GENE, ISOFORM, AND SPLICING REGULATION IN THE DEVELOPING HUMAN BRAIN

Catheter-based renal denervation (RDN) has had mixed results in patients with hypertension. Recently, however, radiofrequency or ultrasound RDN has

Blood Pressure Response to Renal Sympathetic Denervation With Different Ablation Points in Patients With Resistant Hypertension

Alzheimer’s disease (AD) is a neurodegenerative disease that commonly affects the older population whose symptoms are only visible during the later stage which renders the available treatment ineffective. Our study attempts to provide a solution to this problem by identifying urinary biomarkers that could be used in the first-line screening of a larger population for AD before analysing with more sophisticated blood and CSF based biomarkers, which provide high sensitivity on comparison. A systematic review was performed using the keywords “Alzheimer”, “urine”, “biomarkers” and “metabolomics” following the PRISMA criteria, to identify urinary biomarkers for the early diagnosis of Alzheimer’s disease. From the performed study, three metabolites were identified namely 5-hydroxy indole acetic acid, L-arginine and allantoin as biomarkers whose level was altered in AD samples compared to controls. In AD, 5-hydroxy indole acetic acid level was downregulated in urine probably because of the extensive serotonergic denervation that has been observed in the AD brain. Increased levels of L-arginine in the brain which act as a precursor to nitric oxide due to the action of NO synthase might potentially lead to neurotoxicity when present in excess, and is also known to be in synergy with ROS. Increased levels of allantoin in urine is due to the action of increased ROS in the system reacting with uric acid. Here, we provide an overview of all the reported metabolites obtained from the search, by discussing their influence in AD pathology. This study identified three metabolites in urine that could function as potential biomarkers for AD based on significant changes observed between disease and control samples, along with its recurrence and commonality in different models namely mice and human. However, longitudinal and cross-sectional follow-up studies are required for the validation of these biomarkers.

The advent of catheter-based renal denervation held the promise of a procedure-based approach to resistant hypertension. The sham-controlled clinical

Patients with cancer cachexia (CCX) suffer from muscle wasting, which is often but not always accompanied by selective loss of myosin. Here we examined the effects of CCX on muscle mass and myosin heavy chain (MyHC) expression in denervated (DEN) muscles, especially focusing on the protein synthesis and degradation pathways. Male CD2F1 mice were randomly divided into control (CNT) and CCX groups and their left sciatic nerve was transected. CCX was induced by an intraperitoneal injection of colon 26 cells. After 14 days, the serum concentration of IL-6 and corticosteroid was higher in CCX mice than in CNT mice. The combination of CCX with DEN (CCX + DEN) resulted in a marked reduction of the gastrocnemius muscle weight (−69%) that was significantly lower than DEN (−53%) or CCX (−36%) alone. CCX had no effect on MyHC content, but it elicited a preferential MyHC loss when combined with DEN. The expression levels of autophagy markers cathepsin D and LC3BII/I ratio were markedly higher in the CCX + DEN group than in the CNT + DEN and the CCX groups. Paradoxically, there was an increase in protein synthesis rate and phosphorylation levels of p70S6K and rpS6, markers of mTORC1 signaling, in the CNT + DEN group, and these molecular alterations were inhibited in the CCX + DEN group. Our data indicate that CCX aggravates muscle atrophy in DEN muscles by inducing seletive loss of myosin, which involves inactivity dependent mechanisms that is likely to be a consequence of increased autophagy-mediated protein breakdown coupled with impaired protein synthesis.

Patients with atrial fibrillation (AF) frequently also have hypertension. In nonrandomized trials, control of blood pressure (BP) seems to have

Pulmonary artery denervation (PADN) can block local sympathetic nerve of pulmonary artery, reduce the hemodynamic parameters of pulmonary arterial hypertension(PAH), attenuate pulmonary vascular remodeling, right ventricular hypertrophy and fibrosis, thus improving cardiac function.Early basic experiment has determined the position of sympathetic nerve of pulmonary artery in pulmonary endarterium and confirmed the safety and effectiveness of PADN in the animal model of PAH.PADN may play a role by inhibiting execssive activation of the sympathetic nervous system and renin-angiotension-aldosterone system.PADN has been applied to adult clinical research, and has achieved a good clinical effect.On this basis, the possibility of applying PADN to children′s PAH is being explored preliminarily. Key words: Pulmonary arterial hypertension; Pulmonary artery denervation; Autonomic nerve; Child

We showed previously that in anaesthetized rats acute noninvasive renal denervation (DNX) induced an increase in arterial blood pressure (MABP), unlike the usual hypotensive effect. Here we aimed to establish the background of such unusual response, especially the role of oxidative stress as suggested by an earlier study. The contribution of oxidative stress was explored by studying the effects on DNX-induced MABP increase of pretreatment with 4-hydroxy-3-methoxyacetophenone (apocynin, APO), a powerful antioxidant and antihypertensive agent, and N(omega)-propyl-L-arginine (L-NPA), a blocker of neuronal nitric oxide synthase (nNOS). In anaesthetized Wistar rats maintained on standard (STD) or high-salt (HS) diet sequential right- and left-side DNX was performed. MABP responses were examined without pretreatment and after APO (20 mg/day on two preceding days) and L-NPA (1 mg/kg/h throughout experiment), given alone or combined. In untreated rats, bilateral DNX increased MABP by 6% on STD and 15% on HS diet (P < 0.01 or less); the difference between MABP responses was highly significant (P = 0.002). In STD rats APO or APO + L-NPA treatment failed to alter post-DNX MABP increases whereas L-NPA alone reversed the response and a significant 7% decrease occurred. In HS rats APO and L-NPA given alone reversed the MABP response and significant decreases of 14% (P = 0.001) and 8% (P = 0.01), were seen. Surprisingly, with L-NPA + APO pretreatment only abolishment (not reversal) of post-DNX pressure increase occurred. The results suggest that both systemic, intrarenal and brain oxidative stress, and excessive nNOS activity, mostly in the brain, determine the unexpected post-DNX pressure increase.

Although there is good evidence to indicate a major role of intrinsic impairment of the contractile apparatus in muscle weakness seen in several pathophysiological conditions, the factors responsible for control of myofibrillar function are not fully understood. To investigate the role of mechanical load in myofibrillar function, we compared the skinned fiber force between denervated (DEN) and dexamethasone-treated (DEX) rat skeletal muscles with or without neuromuscular electrical stimulation (ES) training. DEN and DEX were induced by cutting the sciatic nerve and daily injection of dexamethasone (5 mg/kg/day) for 7 days, respectively. For ES training, plantarflexor muscles were electrically stimulated to produce four sets of five isometric contractions each day. In situ maximum torque was markedly depressed in the DEN muscles compared to the DEX muscles (-74% vs. -10%), whereas there was not much difference in the degree of atrophy in gastrocnemius muscles between DEN and DEX groups (-24% vs. -17%). Similar results were obtained in the skinned fiber preparation, with a greater reduction in maximum Ca2+-activated force in the DEN than in the DEX group (-53% vs. -16%). Moreover, there was a parallel decline in myosin heavy chain (MyHC) and actin content per muscle volume in DEN muscles, but not in DEX muscles, which was associated with upregulation of NADPH oxidase (NOX) 2, neuronal nitric oxide synthase (nNOS), and endothelial NOS expression, translocation of nNOS from the membrane to the cytosol, and augmentation of mRNA levels of muscle RING finger protein 1 (MuRF-1) and atrogin-1. Importantly, mechanical load evoked by ES protects against DEN- and DEX-induced myofibrillar dysfunction and these molecular alterations. Our findings provide novel insights regarding the difference in intrinsic contractile properties between DEN and DEX and suggest an important role of mechanical load in preserving myofibrillar function in skeletal muscle.