11β-HSD1 determines the extent of muscle atrophy in a model of acute exacerbation of COPD.

Muscle atrophy is an extrapulmonary complication of acute exacerbations (AE) in chronic obstructive pulmonary disease (COPD). The endogenous production and therapeutic application of glucocorticoids (GCs) have been implicated as drivers of muscle loss in AE-COPD. The enzyme 11 β-hydroxysteroid dehydrogenase 1 (11β-HSD1) activates GCs and contributes toward GC-induced muscle wasting.

Effects of a nutritional intervention on impaired behavior and cognitive function in an emphysematous murine model of COPD with endotoxin-induced lung inflammation.

One cluster of the extrapulmonary manifestations in chronic obstructive pulmonary disease (COPD) is related to the brain, which includes anxiety, depression and cognitive impairment. Brain-related comorbidities are related to worsening of symptoms and increased mortality in COPD patients. In this study, a murine model of COPD was used to examine the effects of emphysema and repetitive pulmonary inflammatory events on systemic inflammatory outcomes and brain function.

Brown adipose tissue activation is not related to hypermetabolism in emphysematous chronic obstructive pulmonary disease patients.

Background: Brown adipose tissue (BAT) has been primarily researched as a potential target for mitigating obesity. However, the physiological significance of BAT in relation to cachexia remains poorly understood. The objective of this study was to investigate the putative contribution of BAT on different components of energy metabolism in emphysematous chronic obstructive pulmonary disease (COPD) patients.

Recovery of muscle mass and muscle oxidative phenotype following disuse does not require GSK-3 inactivation.

Background: Physical inactivity contributes to muscle wasting and reductions in mitochondrial oxidative phenotype (OXPHEN), reducing physical performance and quality of life during aging and in chronic disease. Previously, it was shown that inactivation of glycogen synthase kinase (GSK)-3β stimulates muscle protein accretion, myogenesis, and mitochondrial biogenesis. Additionally, GSK-3β is inactivated during recovery of disuse-induced muscle atrophy.

Identification of microRNAs in skeletal muscle associated with lung cancer cachexia.

Background: Cachexia, highly prevalent in patients with non-small cell lung cancer (NSCLC), impairs quality of life and is associated with reduced tolerance and responsiveness to cancer therapy and decreased survival. MicroRNAs (miRNAs) are small non-coding RNAs that play a central role in post-transcriptional gene regulation. Changes in intramuscular levels of miRNAs have been implicated in muscle wasting conditions.

Skeletal muscle unloading results in increased mitophagy and decreased mitochondrial biogenesis regulation.

Introduction: Physical inactivity significantly contributes to loss of muscle mass and performance in bed-bound patients. Loss of skeletal muscle mitochondrial content has been well-established in muscle unloading models, but the underlying molecular mechanism remains unclear. We hypothesized that apparent unloading-induced loss of muscle mitochondrial content is preceded by increased mitophagy- and decreased mitochondrial biogenesis-signaling during the early stages of unloading.

Altered protein turnover signaling and myogenesis during impaired recovery of inflammation-induced muscle atrophy in emphysematous mice.

Exacerbations in Chronic obstructive pulmonary disease (COPD) are often accompanied by pulmonary and systemic inflammation, and are associated with an increased susceptibility to weight loss and muscle wasting. As the emphysematous phenotype in COPD appears prone to skeletal muscle wasting, the aims of this study were to evaluate in emphysematous compared to control mice following repetitive exacerbations (1) changes in muscle mass and strength and, (2) whether muscle mass recovery and its underlying processes are impaired. Emphysema was induced by intra-tracheal (IT) elastase instillations, followed by three weekly IT-LPS instillations to mimic repetitive exacerbations.

Pulmonary inflammation-induced loss and subsequent recovery of skeletal muscle mass require functional poly-ubiquitin conjugation.

Background: Pulmonary inflammation in response to respiratory infections can evoke muscle wasting. Increased activity of the ubiquitin (Ub)-proteasome system (UPS) and the autophagy lysosome pathway (ALP) have been implicated in inflammation-induced muscle atrophy. Since poly-Ub conjugation is required for UPS-mediated proteolysis and has been implicated in the ALP, we assessed the effect of impaired ubiquitin conjugation on muscle atrophy and recovery following pulmonary inflammation, and compared activation and suppression of these proteolytic systems to protein synthesis regulation.

Increased Myogenic and Protein Turnover Signaling in Skeletal Muscle of Chronic Obstructive Pulmonary Disease Patients With Sarcopenia.

Background: Sarcopenia was recently recognized as an independent condition by an International Classification of Diseases, Tenth Revision, Clinical Modification code, and is a frequently observed comorbidity in chronic obstructive pulmonary disease (COPD). Muscle mass is primarily dictated by the balance between protein degradation and synthesis, but their relative contribution to sarcopenia is unclear.

Objective: We aimed to assess potential differential molecular regulation of protein degradation and synthesis, as well as myogenesis, in the skeletal muscle of COPD patients with and without sarcopenia.

Muscle-specific GSK-3β ablation accelerates regeneration of disuse-atrophied skeletal muscle.

Muscle wasting impairs physical performance, increases mortality and reduces medical intervention efficacy in chronic diseases and cancer. Developing proficient intervention strategies requires improved understanding of the molecular mechanisms governing muscle mass wasting and recovery. Involvement of muscle protein- and myonuclear turnover during recovery from muscle atrophy has received limited attention.

Hypoxia differentially regulates muscle oxidative fiber type and metabolism in a HIF-1α-dependent manner.

Loss of skeletal muscle oxidative fiber types and mitochondrial capacity is a hallmark of chronic obstructive pulmonary disease and chronic heart failure. Based on in vivo human and animal studies, tissue hypoxia has been hypothesized as determinant, but the direct effect of hypoxia on muscle oxidative phenotype remains to be established. Hence, we determined the effect of hypoxia on in vitro cultured muscle cells, including gene and protein expression levels of mitochondrial components, myosin isoforms (reflecting slow-oxidative versus fast-glycolytic fibers), and the involvement of the regulatory PPAR/PGC-1α pathway.

Loss of quadriceps muscle oxidative phenotype and decreased endurance in patients with mild-to-moderate COPD.

Being well-established in advanced chronic obstructive pulmonary disease (COPD), skeletal muscle dysfunction and its underlying pathology have been scarcely investigated in patients with mild-to-moderate airflow obstruction. We hypothesized that a loss of oxidative phenotype (oxphen) associated with decreased endurance is present in the skeletal muscle of patients with mild-to-moderate COPD. In quadriceps muscle biopsies from 29 patients with COPD (forced expiratory volume in 1 s [FEV1] 58 ± 16%pred, body mass index [BMI] 26 ± 4 kg/m(2)) and 15 controls (BMI 25 ± 3 kg/m(2)) we assessed fiber type distribution, fiber cross-sectional areas (CSA), oxidative and glycolytic gene expression, OXPHOS protein levels, metabolic enzyme activity, and levels of oxidative stress markers.

Glycogen synthase kinase-3β is required for the induction of skeletal muscle atrophy.

Skeletal muscle atrophy commonly occurs in acute and chronic disease. The expression of the muscle-specific E3 ligases atrogin-1 (MAFbx) and muscle RING finger 1 (MuRF1) is induced by atrophy stimuli such as glucocorticoids or absence of IGF-I/insulin and subsequent Akt signaling. We investigated whether glycogen synthase kinase-3β (GSK-3β), a downstream molecule in IGF-I/Akt signaling, is required for basal and atrophy stimulus-induced expression of atrogin-1 and MuRF1, and myofibrillar protein loss in C(2)C(12) skeletal myotubes.

Palmitate-induced skeletal muscle insulin resistance does not require NF-κB activation.

Palmitate activates the NF-κB pathway, and induces accumulation of lipid metabolites and insulin resistance in skeletal muscle cells. Little information is available whether and how these processes are causally related. Therefore, the objectives were to investigate whether intra-cellular lipid metabolites are involved in FA-induced NF-κB activation and/or insulin resistance in skeletal muscle and to investigate whether FA-induced insulin resistance and NF-κB activation are causally related.

Trans-10, cis-12 conjugated linoleic acid inhibits skeletal muscle differentiation and GLUT4 expression independently from NF-κB activation.

Scope: The capacity of skeletal muscle to contribute to glucose homeostasis depends on muscular insulin sensitivity. The expression of glucose transporter (GLUT)-4 is increased during myoblast differentiation, a process essential in maintenance of adult muscle. Therefore, processes that affect muscle differentiation may influence insulin dependent glucose homeostasis.

Glycogen synthase kinase 3 suppresses myogenic differentiation through negative regulation of NFATc3.

Skeletal muscle atrophy is a prominent and disabling feature in many chronic diseases. Prevention or reversal of muscle atrophy by stimulation of skeletal muscle growth could be an important therapeutic strategy. Glycogen synthase kinase 3beta (GSK-3beta) has been implicated in the negative regulation of skeletal muscle growth.

Myogenic differentiation during regrowth of atrophied skeletal muscle is associated with inactivation of GSK-3beta.

Muscle atrophy contributes to morbidity and mortality in aging and chronic disease, emphasizing the need to gain understanding of the mechanisms involved in muscle atrophy and (re)growth. We hypothesized that the magnitude of muscle regrowth during recovery from atrophy determines whether myonuclear accretion and myogenic differentiation are required and that insulin-like growth factor (IGF)-I/Akt/glycogen synthase kinase (GSK)-3beta signaling differs between regrowth responses. To address this hypothesis we subjected mice to hindlimb suspension (HS) to induce atrophy of soleus (-40%) and plantaris (-27%) muscle.

Muscle wasting and impaired muscle regeneration in a murine model of chronic pulmonary inflammation.

Muscle wasting and increased circulating levels of inflammatory cytokines, including TNF-alpha, are common features of chronic obstructive pulmonary disease. To investigate whether inflammation of the lung is responsible for systemic inflammation and muscle wasting, we adopted a mouse model of pulmonary inflammation resulting from directed overexpression of a TNF-alpha transgene controlled by the surfactant protein C (SP-C) promoter. Compared with wild-type mice, SP-C/TNF-alpha mice exhibited increased levels of TNF-alpha in the circulation and increased endogenous TNF-alpha expression in skeletal muscle, potentially reflecting an amplificatory response to circulating TNF-alpha.

Inhibition of glycogen synthase kinase-3beta activity is sufficient to stimulate myogenic differentiation.

Skeletal muscle atrophy is a prominent and disabling feature of chronic wasting diseases. Prevention or reversal of muscle atrophy by administration of skeletal muscle growth (hypertrophy)-stimulating agents such as insulin-like growth factor I (IGF-I) could be an important therapeutic strategy in these diseases. To elucidate the IGF-I signal transduction responsible for muscle formation (myogenesis) during muscle growth and regeneration, we applied IGF-I to differentiating C(2)C(12) myoblasts and evaluated the effects on phosphatidylinositol 3-kinase (PI3K)/Akt/glycogen synthase kinase-3beta (GSK-3beta) signaling and myogenesis.

Tumor necrosis factor-alpha inhibits myogenic differentiation through MyoD protein destabilization.

Tumor necrosis factor alpha (TNFalpha) has been implicated as a mediator of muscle wasting through nuclear factor kappa B (NF-kappaB) -dependent inhibition of myogenic differentiation. The aim of the present study was to identify the regulatory molecule(s) of myogenesis targeted by TNFalpha/NF-kappaB signaling. TNFalpha interfered with cell cycle exit and repressed the accumulation of transcripts encoding muscle-specific genes in differentiating C2C12 myoblasts.

Enhanced myogenic differentiation by extracellular matrix is regulated at the early stages of myogenesis.

Myogenic cell lines have been used extensively in the study of skeletal muscle development, regeneration, and homeostasis. To induce myogenic differentiation, culture media composed of a wide variety of growth factors and other additives have been used. Because the diversity in these components may modulate the differentiation process differentially, we describe a differentiation protocol that does not require the introduction of any factors to the differentiation media (DM) other than those present in the growth media.

Tumor necrosis factor-alpha inhibits myogenesis through redox-dependent and -independent pathways.

Muscle wasting accompanies diseases that are associated with chronic elevated levels of circulating inflammatory cytokines and oxidative stress. We previously demonstrated that tumor necrosis factor-alpha (TNF-alpha) inhibits myogenic differentiation via the activation of nuclear factor-kappaB (NF-kappaB). The goal of the present study was to determine whether this process depends on the induction of oxidative stress.