BAM 8 (5)1998

Table of Contents




Editorial          346        Cytokines and muscle physiology
                                        KM Byrne     [Full text pdf 8.01Kb]

                          347        Leukaemia Inhibitory Factor and Other Cytokines as Factors Influencing Regeneration  of Skeletal Muscle
                                        John B Kurek, John J. Bower, Jason D. White, Catriona M. Muldoon, and Lawrence Austin   [Full text pdf 469Kb]
 

                          361        Muscle Wasting and IL-6
                                        Toshimasa Tsujinaka, Chikara Ebisui, Junya Fujita, Masanori Kishibuchi, Masahiko Yano and Morito Monden   
                                        [Full text pdf 64.8Kb]
 

                          371        The Role of Tumor Necrosis Factor-ain Muscle Wasting Disorders
                                    Josep M. Argilés, Celia García-Martínez, Marta Llovera and Francisco J. López-Soriano  [Full text pdf 54.3Kb]

                          381        Myo-D Positive Cells Overcome Fibroblasts in Primary Muscle Cultures Grown in the Presence
                                        of a 50-10 kDa  Cytokine Secreted by Macrophages
                                        Emanuele Giurisato, Luciano Dalla Libera, Barbara Ravara, Maria L. Massimino and Marcello  Cantini   
                                        [Full text pdf 853Kb]   


                          389        The Role of Cytotoxic Effector Molecules and Cytokines in Inflammatory Myopathies
                                        Norbert Goebels, Marco DeRossi and Reinhard Hohlfeld    [Full text pdf 45.6Kb]
 
 
 
 

Cytokines and Muscle Physiology

Cytokines are typically discussed in terms of their critical role in the functioning of the immune system. Their importance to other systems, especially muscle physiology, is more recently described. In this special section, the contributors present reviews of their work in the area of cytokines and muscle physiology including growth and disease.

In the immune system, the balance of cytokine expression influences whether a disease state is created or protection against disease prevails. This balance is affected by the type of cytokine produced, the availability of the cytokine to bind receptors, the expression of appropriate receptors, and the response of the target cell. Cytokines can also be expressed in an autocrine or paracrine manner. The contribution of paracrine expression is especially significant in those tissues into which leukocytes migrate, as in the case of inflamed muscle following injury or disease. In many systemic disease states, blood elevations of cytokines can be detected, thus emphasizing the encompassing involvement of cytokines in the disease.

Cytokines have been shown to have a profound role in the loss of muscle mass in many disease states. The exact mechanisms involved are being studied in muscular dystrophy, cancer, AIDS, chronic infections, and inflammatory myopathies, and will give insight into the role of cytokines in normal muscle physiology. From the current investigations, it has been shown that cytokines can affect different stages of myocyte development. Some cytokines can affect the proliferation of myoblasts, while others have been shown to affect the ability of myoblasts to differentiate, including the expression of myogenic proteins and the ability to fuse into myotubes.
The authors contributing to this section have made advances in dissecting the role of cytokines in disease states and in the normal physiology of muscle. Kurek et al. discuss the effect of cytokines on muscle growth. They focus on the role of leukemia inhibitory factor (LIF), but also include a discussion on interleukin-6 (IL-6), transforming growth factor-alpha (TGF-a), and insulin-like growth factor- 1 (IGF- 1). They conclude with a review of gene therapy and myoblast transfer therapy and the possible contributions of cytokines in muscular dystrophy therapy. Monden et al. review the in vitro and in vivo effects of IL-6 on protein balance in muscle. They include sections on the transgenic models used to study cytokine-induced protein degradation and the intracellular processes potentially affected by cytokines. Argiles et al. review the muscle wasting disorders and compare the molecular and cellular differences between different forms. They focus on cytokines produced by macrophages, especially the effects of tumor necrosis factor (TNF) on muscle protein metabolism. Cantini et al. present their latest work on identifying macrophage factors which stimulate the proliferation of myoblasts. Goebels and Hohlfeld present a review on the inflammatory myopathies and the immune mechanisms behind them. They also discuss the role of cytokines in the immunopathogenesis of myopathies.
The review articles included in this section cover a broad spectrum of the effect of cytokines on muscle physiology. We hope that these reviews offer investigators a broad appreciation of this relatively new area of cytokine research and lead to new discussions and new ideas on the possible therapeutic uses of cytokines in muscle disease as well as muscle healing and cellular therapy.

Katherine M. Byrne, Guest Editor
Department of Animal Sciences
Washington State University
Pullman WA, USA


 

Leukaemia Inhibitory Factor and Other Cytokines as Factors Influencing Regeneration of Skeletal Muscle

John B Kurek, John J. Bower(1), Jason D. White(1), Catriona M. Muldoon(1), and Lawrence Austin(1)

Amrad Corporation Ltd., Richmond, Victoria, and (1) Melbourne Neuromuscular Research Centre, St. Vincent’s Hospital, Fitzroy, Victoria, Australi

Abstract

When skeletal muscle is injured, mononuclear muscle precursors, the satellite cells, are activated and begin to proliferate and then fuse with each other to form new multinucleated myotubes, which eventually become the mature muscle fibres. The process of muscle regeneration is regulated by locally produced growth factors that control cellular proliferation and differentiation. Several polypeptide growth factors have been implicated as regulators of myogenic cell proliferation and differentiation during development and after injury. Leukaemia inhibitory factor (LIF), interleukin-6 (IL-6) transforming growth factor-a (TGF-a), basic fibroblast growth factor (bFGF), and insulin like growth factor-1 (IGF-1), are five cytokines which strongly stimulate the proliferation of muscle myoblasts in vitro, with LIF being the most effective. These actions suggest that they have a regulatory role in the development and regeneration of muscle.
The muscle crush model in mice was used to test the effects of these factors in muscle regeneration. Growth factors were administered to injured muscle using osmotic pumps implanted subcutaneously and the growth factor was continuously delivered to the site of injury via a cannula. The results show that LIF greatly increased the rate of muscle regeneration in wild type and LIF knockout mice. LIF stimulated the formation of larger muscle fibres, while not stimulating proliferation of resident fibroblasts. A similar effect was seen when muscle of the mdx mouse was treated with LIF. In contrast, no stimulation of regeneration was seen with IL-6, TGF-a or bFGF. This myotrophic action indicates that LIF contributes to muscle regeneration, and is the only factor to have a positive effect when applied exogenously after injury. Together with its known neurotrophic action, LIF is a potential therapeutic agent for the treatment of neuromuscular disease.
In summary, this review examines the role of growth factors in muscle after injury and demonstrates a significant role for LIF in the regeneration process.

Key words: leukaemia inhibitory factor, interleukin-6, transfonning growth factor-a, insulin like growth factor, fibroblast growth factor, myoblast, muscle regeneration.
Basic Appl. Myol. 8 (5): 347-360, 1998

Muscle Wasting and IL-6

Toshimasa Tsujinaka, Chikara Ebisui(1), Junya Fujita, Masanori Kishibuchi(2), Masahiko Yano, Morito Monden

Department of Surgery II, Osaka University Medical School, (1) Department of Surgery, Hyogo Prefectural Nishinomiya Hospital and (2) Department of Surgery, Kaizuka Municipal Hospital

Abstract

Muscle wasting is a common feature of systemic inflammation and malignant diseases. The primary cause is accelerated proteolysis. Protein degradation was found to be accelerated by IL-6 with activation of intracellular proteases in C2C12 myotubes. IL-6 transgenic mice displayed extensive muscle wasting together with an increase of proteolytic pathways. The increase in activities and mRNA levels of cathepsins (B and L) and the poly-ubiquitin (Ub) mRNA level could be inhibited by treatment with IL-6 receptor antibody (MR16-1), which inhibits the binding of IL-6 to the receptor. Muscle wasting and an increase in the serum IL-6 level were observed with Colon-26 adenocarcinoma. This muscle wasting and increases in the activity and mRNA level of cathepsin L and the poly-Ub mRNA level could be inhibited by MR16-1 treatment via inhibiting the action of IL-6. IL-6 production and atrophy of muscle fibers were induced by intramuscular injection of turpentine oil. The injected muscle displayed increased activities and mRNA levels of cathepsins (B,L). The treatment with MR16-1 suppressed the increase of cathepsin activities.

IL-6 is considered to be a proteolysis-inducing factor due to its modulation of muscle proteolytic systems. IL-6 plays a pivotal role in the muscle wasting observed in systemic inflammation, cancer cachexia and inflammed muscle.

Key words: muscle wasting, IL-6, IL-6 transgenic mouse, IL-6 receptor antibody, proteolytic system, turpentine oil.
Basic Appl. Myol. 8 (5): 361-370, 1998


 

The Role of Tumor Necrosis Factor-a in Muscle Wasting Disorders

Josep M. Argilés, Celia García-Martínez, Marta Llovera and Francisco J. López-Soriano

Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain

Abstract

The present review discusses the role of tumor necrosis factor-a (TNF) in muscle weight loss and protein mobilization during cancer and infection, with special emphasis on the acquired immunodeficiency syndrome (AIDS). It is basically concluded that the most important biochemical event associated with muscle wasting is an enhanced protein degradation through the ubiquitin-dependent proteolytic pathway. TNF is an important activator of this proteolytic system, and future therapeutic approaches for wasting should consider either blocking TNF action or inhibiting the activity of the referred proteolytic system.

Key words: TNF-a, cancer cachexia, AIDS, muscle wasting, cytokines.
Basic Appl. Myol. 8 (5): 371-380, 1998

Myo-D Positive Cells Overcome Fibroblasts in Primary Muscle Cultures Grown in the Presence of a 50-10 kDa Cytokine Secreted by Macrophages

E. Giurisato, L. Dalla Libera(1), B. Ravara(1), M.L. Massimino, M.Cantini

CRIBI Biotechnology Center and Department of Experimental Biomedical Sciences and (1) CNR Unit for Muscle Biology and Physiopathology c/o Department of Experimental Biomedical Sciences, University of Padova, Padova, Italy


Abstract

Recently we demonstrated that in an in vitro culture where both myoblasts and macrophages were grown together, the myotube formation is strongly increased by the presence of an acid stable, heat-labile, soluble growth factor(s) secreted by macrophages. We now present new data concerning the culture medium and the role of macrophages in myoblast proliferation, and in particular we demonstrate that: i) macrophages also release the factor in a totally serum-free medium; ii) muscle growth induced by macrophages is mainly the consequence of an increased myoblast proliferation as revealed by the presence of an increased number of MyoD-positive myonuclei, while fibroblasts show no increase; iii) the muscle specific cytokine(s) released by activated macrophages has a molecular mass in the range 50-10 kDa as determined by both microfiltration and chromatographic experiments.

Key words: macrophage cytokines; MyoD; muscle regeneration; heparin affinity chromatography; myoblast cultures.
Basic Appl. Myol. 8 (5): 381-388, 1998

The Role of Cytotoxic Effector Molecules and Cytokines in Inflammatory Myopathies

Norbert Goebels (1, 2), Marco DeRossi(1), and Reinhard Hohlfeld(1, 2)

(1) Department of Neuroimmunology, Max Planck Institute of Neurobiology, Martinsried and (2) Department of Neurology, Klinikum Grosshadern, University of Munich, Munich, Germany


Abstract

The inflammatory myopathies include dermatomyositis (DM), polymyositis (PM) and inclusion body myositis (IBM). In DM, muscle fiber injury is secondary to an antibody- or immune-complex-mediated immune response against a vascular-endothelial component. In PM and IBM, initially non-necrotic muscle fibers are invaded and eventually destroyed by CD8+ T cells and macrophages. The autoaggressive T cells have the phenotype of activated (HLA-DR+) memory (CD45RO+) cells. T cell receptor (TCR) analyses revealed that the autoaggressive T cells are oligoclonal. In inflammatory lesions, muscle fibers express a number of cytoplasmic and surface molecules that are not detectable in normal muscle fibers. These molecules, which include HLA-class I antigens, heat-shock proteins, adhesion molecules and Fas, are probably induced by locally secreted cytokines. Although many of the muscle fibers invaded by CD8+ T cells express the Fas "death receptor", signs of apoptosis are absent. However, the autoaggressive CD8+ T cells possess perforin-containing granules, which they orient towards the contact zone with the target muscle fiber. This is consistent with a perforin- and secretion-dependent mechanism of muscle fiber injury.

Key words: autoimmunity, cytokines, dermatomyositis, polymyositis.
Basic Appl. Myol. 8 (5): 389-397, 1998