Prevalence of muscle atrophy in pediatric patients during ICU hospitalization.

To evaluate the muscle thickness and prevalence of muscle atrophy of the biceps brachii/brachialis (BB) and quadriceps femoris (QF) in critically ill children using ultrasound (US). The prospective longitudinal study was conducted in the pediatric intensive care unit (PICU) of a tertiary hospital in southern Brazil with children and adolescents of both sexes, aged 1 month to 12 years, on invasive mechanical ventilation for 24 h. US measurements were taken up to 24 h after admission, 72 h after, and weekly until discharge from the PICU. One hundred one patients were selected, of whom 97 underwent two evaluations, 68 three evaluations, and 26 four ultrasound evaluations. The median age was 6 months, with 63 (62.4%) < 1 year old. The most prevalent clinical diagnosis was respiratory diseases (70.3%). There was a reduction in BB thickness from 1 to 2 weeks (- 0.10 cm, p = 0.009) and in QF from 24 h to 2 weeks (- 0.20 cm, p = 0.013) and 72 h to 2 weeks (- 0.18 cm, p = 0.045). The prevalence of muscle atrophy (decrease > 10% in thickness) was 41.2% in at least one muscle group between 24 and 72 h, 39.7% between 24 h and 1 week, and 59.3% between 24 h and 2 weeks. The US allows the evaluation of BB and QF muscle thickness in critically ill children, and monitoring muscles during PICU hospitalization is important. The prevalence of muscle atrophy was 30.8% in the biceps brachii and 46.2% in the quadriceps femoris at the end of 2 weeks of PICU hospitalization, regardless of age and diagnosis. What is Known: • Ultrasound has emerged as a promising method, being a clinically valuable tool for bedside muscle monitoring in critical patients. • Using the ultrasound to measure the muscle thickness in adults has demonstrated good sensitivity for detecting muscle atrophy. However, this method has only been previously validated in few studies with small sample of pediatric patients. What is New: • Using the ultrasound, we observed that critically ill children experienced a loss of muscle thickness and muscle atrophy, especially during the second week of intubation. • The significant prevalence of muscle atrophy at the end of PICU hospitalization highlights the importance of ultrasound in identifying muscle loss.

Impact of combined intermittent fasting and high-intensity interval training on apoptosis and atrophy signaling in rat fast- and slow-twitch muscles.

This study aimed to evaluate the influence of combined intermittent fasting (IF) and high-intensity interval training (HIIT) on morphology, caspase-independent apoptosis signaling pathway, and myostatin expression in soleus and gastrocnemius (white portion) muscles from healthy rats. Sixty-day-old male Wistar rats (n = 60) were divided into four groups: control (C), IF, high-intensity-interval training (T), and high-intensity-interval training and intermittent fasting (T-IF). The C and T groups received ad libitum chow daily; IF and T-IF received the same standard chow every other day. Animals from T and T-IF underwent a HIIT protocol five times a week for 12 weeks. IF reduced gastrocnemius mass and increased pro-apoptotic proteins apoptosis-inducing factor (AIF) and endonuclease G (EndoG) in soleus and cleaved-to-non-cleaved PARP-1 ratio and myostatin expression in gastrocnemius white portion. HIIT increased AIF and apoptosis repressor with caspase recruitment domain expression in soleus and cleaved-to-total PARP-1 ratio in gastrocnemius muscle white portion. The combination of IF and HIIT reduced fiber cross-sectional area in both muscles, increased EndoG and AIF expression, and decreased cleaved-to-non-cleaved PARP-1 ratio in gastrocnemius muscle white portion. Muscle responses to IF and HIIT are directly impacted by the muscle fiber type composition and are modulated, at least in part, by myostatin and caspase-independent apoptosis signaling.

Chikungunya and Mayaro Viruses Induce Chronic Skeletal Muscle Atrophy Triggered by Pro-Inflammatory and Oxidative Response.

Chikungunya (CHIKV) and Mayaro (MAYV) viruses are arthritogenic alphaviruses that promote an incapacitating and long-lasting inflammatory muscle-articular disease. Despite studies pointing out the importance of skeletal muscle (SkM) in viral pathogenesis, the long-term consequences on its physiology and the mechanism of persistence of symptoms are still poorly understood. Combining molecular, morphological, nuclear magnetic resonance imaging, and histological analysis, we conduct a temporal investigation of CHIKV and MAYV replication in a wild-type mice model, focusing on the impact on SkM composition, structure, and repair in the acute and late phases of infection. We found that viral replication and induced inflammation promote a rapid loss of muscle mass and reduction in fiber cross-sectional area by upregulation of muscle-specific E3 ubiquitin ligases MuRF1 and Atrogin-1 expression, both key regulators of SkM fibers atrophy. Despite a reduction in inflammation and clearance of infectious viral particles, SkM atrophy persists until 30 days post-infection. The genomic CHIKV and MAYV RNAs were still detected in SkM in the late phase, along with the upregulation of chemokines and anti-inflammatory cytokine expression. In agreement with the involvement of inflammatory mediators on induced atrophy, the neutralization of TNF and a reduction in oxidative stress using monomethyl fumarate, an agonist of Nrf2, decreases atrogen expression and atrophic fibers while increasing weight gain in treated mice. These data indicate that arthritogenic alphavirus infection could chronically impact body SkM composition and also harm repair machinery, contributing to a better understanding of mechanisms of arthritogenic alphavirus pathogenesis and with a description of potentially new targets of therapeutic intervention.

Myogenic microRNAs as Therapeutic Targets for Skeletal Muscle Mass Wasting in Breast Cancer Models.

Breast cancer is the type of cancer with the highest prevalence in women worldwide. Skeletal muscle atrophy is an important prognostic factor in women diagnosed with breast cancer. This atrophy stems from disrupted skeletal muscle homeostasis, triggered by diminished anabolic signalling and heightened inflammatory conditions, culminating in an upregulation of skeletal muscle proteolysis gene expression. The importance of delving into research on modulators of skeletal muscle atrophy, such as microRNAs (miRNAs), which play a crucial role in regulating cellular signalling pathways involved in skeletal muscle protein synthesis and degradation, has been recognised. This holds true for conditions of homeostasis as well as pathologies like cancer. However, the determination of specific miRNAs that modulate skeletal muscle atrophy in breast cancer conditions has not yet been explored. In this narrative review, we aim to identify miRNAs that could directly or indirectly influence skeletal muscle atrophy in breast cancer models to gain an updated perspective on potential therapeutic targets that could be modulated through resistance exercise training, aiming to mitigate the loss of skeletal muscle mass in breast cancer patients.

Malnutrition: muscle wasting, inflammation, RDW, and their relation with adverse outcomes.

OBJECTIVE: The objective of the study was to explore red cell distribution width (RDW) as a surrogate marker of inflammation, alone and in conjunction with muscle wasting to predict malnutrition-related adverse outcomes. METHODS: This was a single-center observational study including adult hospitalized patients. Demographic variables, malnutrition criteria, and RDW were captured within 24 hours of hospital admission. Correlation tests and regression models were performed between these variables (RDW and muscle wasting) and adverse outcomes (in-hospital mortality and unplanned transfer to critical care areas (CCA). RESULTS: Five hundred and forty-five patients were included in the final analysis. Muscle wasting showed an independent association with adverse outcomes in every regression model tested. RDW alone showed fair predictive performance for both outcomes' significance and the adjusted model with muscle wasting showed association only for unplanned transfer to CCA. CONCLUSION: RDW did not improve the prediction of adverse outcomes compared to muscle wasting assessed by physical examination and simple indexes for acute and chronic inflammation. Malnourished patients presented higher RDW values showing a possible metabolic profile (higher inflammation and lower muscle). It is still unknown whether nutrition support can influence RDW value over time as a response marker or if RDW can predict who may benefit the most from nutritional support.

OBJETIVO: Explorar el ancho de distribución eritrocitaria (ADE) como un marcador subrogado de inflamación, individualmente y en conjunto con el desgaste muscular, para predecir resultados adversos asociados a la desnutrición. MÉTODO: Estudio unicéntrico, observacional, incluyendo pacientes adultos hospitalizados. Se capturaron variables demográficas, criterios de desnutrición y el ADE en las primeras 24 horas de ingreso. Se realizaron pruebas de correlación y modelos de regresión entre dichas variables (ADE y desgaste) y resultados adversos (mortalidad hospitalaria y traslado no planeado a áreas críticas). RESULTADOS: Se incluyeron 545 pacientes. El desgaste muscular mostró asociación independiente con los resultados adversos en cada modelo. El ADE individualmente mostró un desempeño aceptable para la predicción de ambos resultados, y en modelos ajustados con desgaste muscular mostró asociación únicamente con traslado no planeado a áreas críticas. CONCLUSIONES: El ADE no mejoró la predicción de resultados adversos comparado con el desgaste muscular por exploración física e índices simples de inflamación. Los pacientes con desnutrición presentaron mayores valores de ADE, mostrando un posible perfil metabólico (mayor inflamación y menos músculo). Aún se desconoce si el soporte nutricional puede influenciar el ADE como un marcador de respuesta o si puede predecir una respuesta favorable al soporte nutricional.

Reduced sympathetic activity is associated with the development of pain and muscle atrophy in a female rat model of fibromyalgia.

Fibromyalgia (FM) is characterized by chronic widespread musculoskeletal pain accompanied by fatigue and muscle atrophy. Although its etiology is not known, studies have shown that FM patients exhibit altered function of the sympathetic nervous system (SNS), which regulates nociception and muscle plasticity. Nevertheless, the precise SNS-mediated mechanisms governing hyperalgesia and skeletal muscle atrophy in FM remain unclear. Thus, we employed two distinct FM-like pain models, involving intramuscular injections of acidic saline (pH 4.0) or carrageenan in prepubertal female rats, and evaluated the catecholamine content, adrenergic signaling and overall muscle proteolysis. Subsequently, we assessed the contribution of the SNS to the development of hyperalgesia and muscle atrophy in acidic saline-injected rats treated with clenbuterol (a selective ß2-adrenergic receptor agonist) and in animals maintained under baseline conditions and subjected to epinephrine depletion through adrenodemedullation (ADM). Seven days after inducing an FM-like model with acidic saline or carrageenan, we observed widespread mechanical hyperalgesia along with loss of strength and/or muscle mass. These changes were associated with reduced catecholamine content, suggesting a common underlying mechanism. Notably, treatment with a ß2-agonist alleviated hyperalgesia and prevented muscle atrophy in acidic saline-induced FM-like pain, while epinephrine depletion induced mechanical hyperalgesia and increased muscle proteolysis in animals under baseline conditions. Together, the results suggest that reduced sympathetic activity is involved in the development of pain and muscle atrophy in the murine model of FM analyzed.

Doxorubicin causes cachexia, sarcopenia, and frailty characteristics in mice.

While chemotherapy treatment can be lifesaving, it also has adverse effects that negatively impact the quality of life. To investigate the effects of doxorubicin chemotherapy on body weight loss, strength and muscle mass loss, and physical function impairments, all key markers of cachexia, sarcopenia, and frailty. Seventeen C57/BL/6 mice were allocated into groups. 1) Control (n = 7): mice were exposed to intraperitoneal (i.p.) injections of saline solution. 2) Dox (n = 10): mice were exposed to doxorubicin chemotherapy cycles (total dose of 18 mg/kg divided over 15 days). The body weight loss and decreased food intake were monitored to assess cachexia. To assess sarcopenia, we measured muscle strength loss using a traction method and evaluated muscle atrophy through histology of the gastrocnemius muscle. To evaluate physical function impairments and assess frailty, we employed the open field test to measure exploratory capacity. Doxorubicin administration led to the development of cachexia, as evidenced by a significant body weight loss (13%) and a substantial decrease in food intake (34%) over a 15-day period. Furthermore, 90% of the mice treated with doxorubicin exhibited sarcopenia, characterized by a 20% reduction in traction strength (p<0,05), a 10% decrease in muscle mass, and a 33% reduction in locomotor activity. Importantly, all mice subjected to doxorubicin treatment were considered frail based on the evaluation of their overall condition and functional impairments. The proposed model holds significant characteristics of human chemotherapy treatment and can be useful to understand the intricate relationship between chemotherapy, cachexia, sarcopenia, and frailty.

Movement Disorder Perspectives on Monocarboxylate 8 Deficiency: A Case Series of 3 Colombian Patients with Allan-Herndon-Dudley Syndrome.

BACKGROUND: Deficiencies in the thyroid hormone transporter monocarboxylate 8 (MCT8) due to pathogenic variants in the SLC16A2 gene (OMIM 300095) result in a complex phenotype with main endocrine and neurologic symptoms. This rare disorder, named Allan-Herndon-Dudley syndrome (AHDS) (OMIM 300523), is inherited in an X-linked trait. One of the prominent features of AHDS is the presence of movement disorders (MD), which are complex and carry a significant burden of the disease. CASES: Patient 1: male with hypotonia since birth, developmental delay, dystonic posturing at 4 months and at 15 months, and startle reaction developed with sensory stimuli. Patient 2: male, at 2 months, shows hypotonia and developmental delay, paroxysmal episodes triggered by a stimulus with sudden blush, tonic asymmetric posture, and no epileptiform activity. At 10 months, generalized dystonic posturing. Patient 3: typical neurodevelopmental milestones until 6 months; at 24 months, dystonia, startle reaction, and upper motoneuron signs. CONCLUSIONS: We aim to describe our patients diagnosed with AHDS, focusing on MD phenomenology and strengthening the phenotype-genotype correlations for this rare condition.

Adrenalectomy attenuates hyperalgesia but does not regulate muscle wasting in a female rat model of fibromyalgia.

Although it is well established that fibromyalgia (FM) syndrome is characterized by chronic diffuse musculoskeletal hyperalgesia, very little is known about the effect of this pathology on muscle tissue plasticity. Therefore, the present study aimed to characterize the putative alterations in skeletal muscle mass in female rats subjected to a FM model by inducing chronic diffuse hyperalgesia (CDH) through double injections of acidic saline (pH 4.0) into the left gastrocnemius muscle at 5-day intervals. To determine protein turnover, the total proteolysis, proteolytic system activities and protein synthesis were evaluated in oxidative soleus muscles of pH 7.2 (control) and pH 4.0 groups at 7 days after CDH induction. All animals underwent behavioural analyses of mechanical hyperalgesia, strength and motor performance. Our results demonstrated that, in addition to hyperalgesia, rats injected with acidic saline exhibited skeletal muscle loss, as evidenced by a decrease in the soleus fibre cross-sectional area. This muscle loss was associated with increased proteasomal proteolysis and expression of the atrophy-related gene (muscle RING-finger protein-1), as well as reduced protein synthesis and decreased protein kinase B/S6 pathway activity. Although the plasma corticosterone concentration did not differ between the control and pH 4.0 groups, the removal of the adrenal glands attenuated hyperalgesia, but it did not prevent the increase in muscle protein loss in acidic saline-injected animals. The data suggests that the stress-related hypothalamic-pituitary-adrenal axis is involved in the development of hyperalgesia, but is not responsible for muscle atrophy observed in the FM model induced by intramuscular administration of acidic saline. Although the mechanisms involved in the attenuation of hyperalgesia in rats injected with acidic saline and subjected to adrenalectomy still need to be elucidated, the results found in this study suggest that glucocorticoids may not represent an effective therapeutic approach to alleviate FM symptoms.

Effects of amino acid supplementation on muscle mass, muscle performance and functional capacity in subjects undergoing total knee arthroplasty: a systematic review of randomized clinical trials.

The aim of the present study was to summarize the effectiveness of amino acid supplementation on muscle strength, muscle volume, and functional capacity in patients undergoing total knee arthroplasty. For this, in November 2022, a search was carried out in the PubMed, Cochrane Library, and EMBASE databases, identifying a total of 2182 documents, of which only 4 were included in the present review. The included studies had 148 participants (47 men and 101 women), with a minimum age of 53 and a maximum of 92 years, and supplementation times of 13 to 30 days (1 to 3 times a day). For the results, in relation to muscle performance, when comparing the control and experimental groups, greater muscle atrophy was observed in the pre- and post-moments of the control group, in relation to the experimental group. In addition, studies suggest a good tendency for muscle mass gain, and improvement in the functional capacities of patients who used supplementation. Therefore, the use of amino acids after TKA surgery reduces muscle atrophy, which preserves muscle mass and leads to better performance in tests of strength and functional capacity, when compared to the use of a placebo.

New Trends to Treat Muscular Atrophy: A Systematic Review of Epicatechin.

Epicatechin is a polyphenol compound that promotes skeletal muscle differentiation and counteracts the pathways that participate in the degradation of proteins. Several studies present contradictory results of treatment protocols and therapeutic effects. Therefore, the objective of this systematic review was to investigate the current literature showing the molecular mechanism and clinical protocol of epicatechin in muscle atrophy in humans, animals, and myoblast cell-line. The search was conducted in Embase, PubMed/MEDLINE, Cochrane Library, and Web of Science. The qualitative analysis demonstrated that there is a commonness of epicatechin inhibitory action in myostatin expression and atrogenes MAFbx, FOXO, and MuRF1. Epicatechin showed positive effects on follistatin and on the stimulation of factors related to the myogenic actions (MyoD, Myf5, and myogenin). Furthermore, the literature also showed that epicatechin can interfere with mitochondrias' biosynthesis in muscle fibers, stimulation of the signaling pathways of AKT/mTOR protein production, and amelioration of skeletal musculature performance, particularly when combined with physical exercise. Epicatechin can, for these reasons, exhibit clinical applicability due to the beneficial results under conditions that negatively affect the skeletal musculature. However, there is no protocol standardization or enough clinical evidence to draw more specific conclusions on its therapeutic implementation.

Soluble Factors Associated with Denervation-induced Skeletal Muscle Atrophy.

Skeletal muscle tissue has the critical function of mechanical support protecting the body. In addition, its functions are strongly influenced by the balanced synthesis and degradation processes of structural and regulatory proteins. The inhibition of protein synthesis and/or the activation of catabolism generally determines a pathological state or condition called muscle atrophy, a reduction in muscle mass that results in partial or total loss of function. It has been established that many pathophysiological conditions can cause a decrease in muscle mass. Skeletal muscle innervation involves stable and functional neural interactions with muscles via neuromuscular junctions and is essential for maintaining normal muscle structure and function. Loss of motor innervation induces rapid skeletal muscle fiber degeneration with activation of atrophy-related signaling and subsequent disassembly of sarcomeres, altering normal muscle function. After denervation, an inflammation stage is characterized by the increased expression of pro-inflammatory cytokines that determine muscle atrophy. In this review, we highlighted the impact of some soluble factors on the development of muscle atrophy by denervation.

Unilateral Hypofunction of the Masseter Leads to Molecular and 3D Morphometric Signs of Atrophy in Ipsilateral Agonist Masticatory Muscles in Adult Mice.

Mice are commonly used to study mandibular dynamics due to their similarity in chewing cycle patterns with humans. Adult mice treated unilaterally with botulinum toxin type A (BoNTA) in the masseter exhibit atrophy of this muscle characterized by an increase in the gene expression of atrophy-related molecular markers, and a reduction in both muscle fiber diameter and muscle mass at 14d. However, the impact of this muscle imbalance on the non-treated masticatory muscles remains unexplored. Here, we hypothesize that the unilateral masseter hypofunction leads to molecular and 3D morphometric signs of atrophy of the masseter and its agonist masticatory muscles in adult mice. Twenty-three 8-week-old male BALB/c mice received a single injection of BoNTA in the right masseter, whereas the left masseter received the same volume of saline solution (control side). Animals were euthanized at 2d, 7d, and 14d, and the masticatory muscles were analyzed for mRNA expression. Five heads were harvested at 14d, fixed, stained with a contrast-enhanced agent, and scanned using X-ray microtomography. The three-dimensional morphometric parameters (the volume and thickness) from muscles in situ were obtained. Atrogin-1/MAFbx, MuRF-1, and Myogenin mRNA gene expression were significantly increased at 2 and 7d for both the masseter and temporalis from the BoNTA side. For medial pterygoid, increased mRNA gene expression was found at 7d for Atrogin-1/MAFbx and at 2d-7d for Myogenin. Both the volume and thickness of the masseter, temporalis, and medial pterygoid muscles from the BoNTA side were significantly reduced at 14d. In contrast, the lateral pterygoid from the BoNTA side showed a significant increase in volume at 14d. Therefore, the unilateral hypofunction of the masseter leads to molecular and morphological signs of atrophy in both the BoNTA-injected muscle and its agonistic non-injected masticatory muscles. The generalized effect on the mouse masticatory apparatus when one of its components is intervened suggests the need for more clinical studies to determine the safety of BoNTA usage in clinical dentistry.

Ultrasound assessment of muscle mass and correlation with clinical outcomes in critically ill patients: a prospective observational study.

PURPOSE: Muscular atrophy implies structural and functional alterations related to muscular force production and movement. This condition has been reported to be the main reason for generalized muscle weakness; it reflects the severity of the disease and can have a profound impact on short- and long-term clinical outcomes. The purpose of this study was to determine whether muscle atrophy ultrasound parameters early predict muscle weakness, morbidity, or 28-days mortality. METHODS: This was a prospective, observational single center cohort study. Ultrasound was used to determine the cross-sectional area and muscle thickness of the rectus femoris on the first and third day of ICU stay. The main outcome was the incidence of significant muscle atrophy (≥ 10%). RESULTS: Ultrasound measurements were made in 31 patients, 58% (18/31) of which showed significant muscle atrophy. The relative loss of muscle mass per day was 1.78 at 5% per day. The presence of muscle atrophy presents increased risk for limb muscle weakness and handgrip weakness. The 28-days mortality rate was similar in both subgroups. CONCLUSION: The presence of muscle atrophy presents an increased clinical risk for the development of limb ICUAW and handgrip, although these observations were not statistically significant. The results could be used to plan future studies on this topic.

Urinary metabolomic biomarker candidates for skeletal muscle wasting in patients with rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease that affects the joints, leading to chronic synovial inflammation and local tissue destruction. Extra-articular manifestations may also occur, such as changes in body composition. Skeletal muscle wasting is often observed in patients with RA, but methods for assessing loss of muscle mass are expensive and not widely available. Metabolomic analysis has shown great potential for identifying changes in the metabolite profile of patients with autoimmune diseases. In this setting, urine metabolomic profiling in patients with RA may be a useful tool to identify skeletal muscle wasting. METHODS: Patients aged 40-70 years with RA have been recruited according to the 2010 ACR/EULAR classification criteria. Further, the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) determined the disease activity. The muscle mass was measured by Dual X-ray absorptiometry (DXA) to generate the appendicular lean mass index (ALMI) by summing the lean mass measurements for both arms and legs and dividing them by height squared (kg/height2 ). Finally, urine metabolomic analysis by 1 H nuclear magnetic resonance (1 H-NMR) spectroscopy was performed and the metabolomics data set analysed using the BAYESIL and MetaboAnalyst software packages. Principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) were applied to the 1 H-NMR data, followed by Spearman's correlation analysis. The combined receiver operating characteristic curve (ROC) was calculated, as well as the logistic regression analyses to establish a diagnostic model. The significance level at P < 0.05 was set for all analyses. RESULTS: The total set of subjects investigated included 90 patients with RA. Most patients were women (86.7%), with a mean age of 56.5 ± 7.3 years old and a median DAS28-CRP of 3.0 (IQR 1.0-3.0). Fifteen metabolites were identified in the urine samples with high variable importance in projection (VIP scores) by MetaboAnalyst. Of these, dimethylglycine (r = 0.205; P = 0.053), oxoisovalerate (r = -0.203; P = 0.055), and isobutyric acid (r = -0.249; P = 0.018) were significantly correlated with ALMI. Based on the low muscle mass (ALMI ≤6.0 kg/m2 for women and ≤8.1 kg/m2 for men) a diagnostic model have been established with dimethylglycine (area under the curve [AUC] = 0.65), oxoisovalerate (AUC = 0.49), and isobutyric acid (AUC = 0.83) with significant sensitivity and specificity. CONCLUSIONS: Isobutyric acid, oxoisovalerate, and dimethylglycine from urine samples were associated with low skeletal muscle mass in patients with RA. These findings suggest that this group of metabolites may be further tested as biomarkers for identification of skeletal muscle wasting.

Skeletal Muscle Atrophy Induced by Diabetes Is Mediated by Non-Selective Channels and Prevented by Boldine.

Individuals with diabetes mellitus present a skeletal muscle myopathy characterized by atrophy. However, the mechanism underlying this muscular alteration remains elusive, which makes it difficult to design a rational treatment that could avoid the negative consequences in muscles due to diabetes. In the present work, the atrophy of skeletal myofibers from streptozotocin-induced diabetic rats was prevented with boldine, suggesting that non-selective channels inhibited by this alkaloid are involved in this process, as has previously shown for other muscular pathologies. Accordingly, we found a relevant increase in sarcolemma permeability of skeletal myofibers of diabetic animals in vivo and in vitro due to de novo expression of functional connexin hemichannels (Cx HCs) containing connexins (Cxs) 39, 43, and 45. These cells also expressed P2X7 receptors, and their inhibition in vitro drastically reduced sarcolemma permeability, suggesting their participation in the activation of Cx HCs. Notably, sarcolemma permeability of skeletal myofibers was prevented by boldine treatment that blocks Cx43 and Cx45 HCs, and now we demonstrated that it also blocks P2X7 receptors. In addition, the skeletal muscle alterations described above were not observed in diabetic mice with myofibers deficient in Cx43/Cx45 expression. Moreover, murine myofibers cultured for 24 h in high glucose presented a drastic increase in sarcolemma permeability and levels of NLRP3, a molecular member of the inflammasome, a response that was also prevented by boldine, suggesting that, in addition to the systemic inflammatory response found in diabetes, high glucose can promote the expression of functional Cx HCs and activation of the inflammasome in skeletal myofibers. Therefore, Cx43 and Cx45 HCs play a critical role in myofiber degeneration, and boldine could be considered a potential therapeutic agent to treat muscular complications due to diabetes.

Effects of exercise training on glucocorticoid-induced muscle atrophy: Literature review.

Glucocorticoids (GCs) administration, such as cortisol acetate (CA) and dexamethasone (DEXA), is used worldwide due to their anti-inflammatory, anti-allergic, and immunosuppressive properties. However, muscle atrophy is one of the primary deleterious induced responses from the chronic treatment with GCs since it stimulates muscle degradation inhibiting muscle protein synthesis. Animal models allow a better understanding of the molecular pathways involved in this process of gene modulation and production of hypertrophic and atrophic proteins. The treatment with GCs, such as DEXA, promotes the reduction of hypertrophic proteins such as serine/threonine tyrosine kinase (AKT), protein kinase mammalian target of rapamycin (mTOR), and ribosomal protein S6 kinase (p70S6K) and increased gene expression or production of atrophic proteins, such as myostatin, muscle atrophic F-box (atrogin-1), or muscle ring finger protein-1 (MuRF-1). In both continuous exercise (CE) and resistance exercise (RE) forms, exercise training is used to mitigate muscle atrophy induced by GCs. The CE attenuated muscle atrophy induced by CA or DEXA in the plantaris and extensor digitorum longus muscles, while RE mitigated the DEXA-induced atrophy in plantaris and flexor hallucis longus muscles. The RE response appears to have occurred by modulation of hypertrophic proteins through increased protein production or phosphorylated/total ratio of mTOR and p70S6K and decreased atrophic protein production of MuRF-1. CE needs future research to understand the molecular pathways of its protective response.