Antioxidants Reduce Muscular Dystrophy in the Mouse Model of Laminin α2 Chain-Deficient Muscular Dystrophy.

Congenital muscular dystrophy with laminin α2 chain-deficiency (LAMA2-CMD) is a severe neuromuscular disorder without a cure. Using transcriptome and proteome profiling as well as functional assays, we previously demonstrated significant metabolic impairment in skeletal muscle from LAMA2-CMD patients and mouse models. Reactive oxygen species (ROS) increase when oxygen homeostasis is not maintained and, here, we investigate whether oxidative stress indeed is involved in the pathogenesis of LAMA2-CMD.

Effects of metformin on congenital muscular dystrophy type 1A disease progression in mice: a gender impact study.

Congenital muscular dystrophy with laminin α2 chain-deficiency (LAMA2-CMD) is a severe muscle disorder with complex underlying pathogenesis. We have previously employed profiling techniques to elucidate molecular patterns and demonstrated significant metabolic impairment in skeletal muscle from LAMA2-CMD patients and mouse models. Thus, we hypothesize that skeletal muscle metabolism may be a promising pharmacological target to improve muscle function in LAMA2-CMD.

Bioenergetic Impairment in Congenital Muscular Dystrophy Type 1A and Leigh Syndrome Muscle Cells.

Skeletal muscle has high energy requirement and alterations in metabolism are associated with pathological conditions causing muscle wasting and impaired regeneration. Congenital muscular dystrophy type 1A (MDC1A) is a severe muscle disorder caused by mutations in the LAMA2 gene. Leigh syndrome (LS) is a neurometabolic disease caused by mutations in genes related to mitochondrial function.

Skeletal muscle wasting and renewal: a pivotal role of myokine IL-6.

Adult skeletal tissue is composed of heterogeneous population of cells that constantly self-renew by means of a controlled process of activation and proliferation of tissue-resident stem cells named satellite cells. Many growth factors, cytokines and myokines produced by skeletal muscle cells play critical roles in local regulation of the inflammatory process and skeletal muscle regeneration during different pathological conditions. IL-6 is a pleiotropic cytokine released in large amount during infection, autoimmunity and cancer.

Dermcidin exerts its oncogenic effects in breast cancer via modulation of ERBB signaling.

Background: We previously identified dermicidin (DCD), which encodes a growth and survival factor, as a gene amplified and overexpressed in a subset of breast tumors. Patients with DCD-positive breast cancer have worse prognostic features. We therefore searched for specific molecular signatures in DCD-positive breast carcinomas from patients and representative cell lines.

Cachexia: a problem of energetic inefficiency.

An alteration of energy balance is the immediate cause of the so-called cachexia. Although alterations of energy intake are often associated with cachexia, it has lately became clear that an increased energy expenditure is the main cause of wasting associated with different types of pathological conditions, such as cancer, infections or chronic heart failure among others. Different types of molecular mechanisms contribute to energy expenditure and, therefore, involuntary body weight loss; among them, adenosine triphosphate (ATP) consumption by sarcoplasmic reticulum Ca(2+) pumps could represent a key mechanism.

Quantitative proteomic analysis reveals metabolic alterations, calcium dysregulation, and increased expression of extracellular matrix proteins in laminin α2 chain-deficient muscle.

Congenital muscular dystrophy with laminin α2 chain deficiency (MDC1A) is one of the most severe forms of muscular disease and is characterized by severe muscle weakness and delayed motor milestones. The genetic basis of MDC1A is well known, yet the secondary mechanisms ultimately leading to muscle degeneration and subsequent connective tissue infiltration are not fully understood. In order to obtain new insights into the molecular mechanisms underlying MDC1A, we performed a comparative proteomic analysis of affected muscles (diaphragm and gastrocnemius) from laminin α2 chain-deficient dy(3K)/dy(3K) mice, using multidimensional protein identification technology combined with tandem mass tags.

Bortezomib partially improves laminin α2 chain-deficient muscular dystrophy.

Congenital muscular dystrophy, caused by mutations in LAMA2 (the gene encoding laminin α2 chain), is a severe and incapacitating disease for which no therapy is yet available. We have recently demonstrated that proteasome activity is increased in laminin α2 chain-deficient muscle and that treatment with the nonpharmaceutical proteasome inhibitor MG-132 reduces muscle pathology in laminin α2 chain-deficient dy(3K)/dy(3K) mice. Here, we explore the use of the selective and therapeutic proteasome inhibitor bortezomib (currently used for treatment of relapsed multiple myeloma and mantle cell lymphoma) in dy(3K)/dy(3K) mice and in congenital muscular dystrophy type 1A muscle cells.

Skeletal muscle mitochondrial uncoupling in a murine cancer cachexia model.

Approximately half of all cancer patients present with cachexia, a condition in which disease-associated metabolic changes lead to a severe loss of skeletal muscle mass. Working toward an integrated and mechanistic view of cancer cachexia, we investigated the hypothesis that cancer promotes mitochondrial uncoupling in skeletal muscle. We subjected mice to in vivo phosphorous-31 nuclear magnetic resonance (31P NMR) spectroscopy and subjected murine skeletal muscle samples to gas chromatography/mass spectrometry (GC/MS).

A differential pattern of gene expression in skeletal muscle of tumor-bearing rats reveals dysregulation of excitation–contraction coupling together with additional muscle alterations.

Introduction: Cachexia is a wasting condition that manifests in several types of cancer. The main characteristic of this condition is a profound loss of muscle mass.

Methods: By using a microarray system, expression of several hundred genes was screened in skeletal muscle of rats bearing a cachexia-inducing tumor, the AH-130 Yoshida ascites hepatoma.

Mitochondrial and sarcoplasmic reticulum abnormalities in cancer cachexia: altered energetic efficiency?

Background: Cachexia is a wasting condition that manifests in several types of cancer, and the main characteristic is the profound loss of muscle mass.

Methods: The Yoshida AH-130 tumor model has been used and the samples have been analyzed using transmission electronic microscopy, real-time PCR and Western blot techniques.

Results: Using in vivo cancer cachectic model in rats, here we show that skeletal muscle loss is accompanied by fiber morphologic alterations such as mitochondrial disruption, dilatation of sarcoplasmic reticulum and apoptotic nuclei.

Interleukin-15 affects differentiation and apoptosis in adipocytes: implications in obesity.

Interleukin-15 (IL-15) is an anabolic factor for skeletal muscle and several reports have described its important role as a regulator of energy homeostasis. In this study, we analyzed the effects of IL-15 on adipocyte differentiation using the 3T3-L1 preadipose cell line. The data show that IL-15 tends to reduce the rate of adipocyte proliferation, induces apoptosis, and partially stops differentiation.

Patterns of gene expression in muscle and fat in tumor-bearing rats: effects of CRF2R agonist on cachexia.

The hypothesis we tested was that administering corticotropin-releasing factor receptor agonists preserves muscle mass during cancer that is related to changes in tissue gene expression. cDNA microarrays were used to compare mRNAs from muscle and adipose tissues of non-treated and agonist-treated tumor-bearing rats. In muscle of non-tumor-bearing agonist-treated animals we observed decreased expression of genes associated with fatty acid uptake and esterification.