Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Immunology, Endocrine and Metabolic Agents) - Volume 10, Issue 4, 2010

It has now been 13 years since the original report in 1997 of the discovery of myostatin and its function as a negative regulator of muscle mass [1]. Since that initial report, an enormous amount of effort in both the academic and the biotechnology/pharmaceutical research communities has been directed at understanding the biology of myostatin and developing strategies for exploiting its biological activity for clinical applications. A PubMed search with the term “myostatin” now lists almost 900 papers, and collectively, these papers have provided numerous insights into the regulation and function of myostatin as well as the consequences of manipulating myostatin activity in both normal and disease settings. These insights have fueled the development of therapeutic agents targeting this signaling pathway, and at least four companies have entered clinical trials with myostatin inhibitors to combat muscle loss. In this issue of Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry, we have assembled a group of thought leaders to review and assess the progress that has been made to date in this field. In the first article in this collection, I summarize what is currently known about the mechanisms by which myostatin activity is regulated extracellularly by inhibitory binding proteins, and I discuss the implications of these regulatory mechanisms both with respect to therapeutic development and with respect to the physiological function of myostatin in regulating the balance between muscle and fat. The second article, written by Anthony Otto, Antonios Matsakas, and Ketan Patel, addresses the role of myostatin in regulating myogenesis. The authors synthesize data obtained in multiple species regarding the expression pattern of myostatin during development, the mechanisms by which myostatin expression is regulated, and the function of myostatin in establishing the proper numbers and types of muscle fibers. This article is followed by two articles describing potential applications of targeting the myostatin pathway for treating muscle degenerative and wasting conditions. In the first, Kathryn Wagner summarizes efforts to date investigating the potential beneficial effects of blocking myostatin signaling in various neuromuscular diseases, including muscular dystrophy, spinal muscular atrophy, and amyotropic lateral sclerosis. In the second, Hilary Wilkinson summarizes what is known about the role that myostatin may play in age-related muscle loss, or sarcopenia, and the effects of inhibiting this pathway in rodent models of sarcopenia. The fact that levels of myostatin signaling can have such profound effects on overall muscle mass has implications for the physiology of muscle not only in terms of its contractile function but also in terms of its metabolic activity, the latter of which is the focus of the next two articles. In one article, Alexandra McPherron reviews what is known about the metabolic functions of myostatin and the highly related protein, GDF-11, and in the other, Powen Tu, Shalender Bhasin, and Wen Guo discuss the cardiometabolic effects of myostatin inhibition. In the final article in this collection, Michel Georges summarizes the enormous amount of data that have been obtained from multiple species in which naturally occurring myostatin mutations have been identified and discusses the prospects of targeting myostatin signaling for livestock production.

Myostatin (MSTN) is a transforming growth factor-β family member that plays a critical role in regulating skeletal muscle mass. Genetic studies in multiple species have demonstrated that mutations in the Mstn gene lead to dramatic and widespread increases in muscle mass as a result of a combination of increased fiber numbers and increased fiber sizes. MSTN inhibitors have also been shown to cause significant increases in muscle growth when administered to adult mice. As a result, there has been an extensive effort to understand the mechanisms underlying MSTN regulation and activity with the goal of developing the most effective strategies for targeting this signaling pathway for clinical applications. Here, I review the current state of knowledge regarding the regulation of MSTN extracellularly by binding proteins and discuss the implications of these findings both with respect to the fundamental physiological role that MSTN plays in regulating tissue homeostasis and with respect to the development of therapeutic agents to combat muscle loss.

Myostatin is a key negative regulator of skeletal muscle mass development in vertebrates. Recent studies have vastly expanded our understanding of the cellular and molecular mechanisms by which Myostatin acts to regulate the size of skeletal muscle within the vertebrate body. In order to understand the origins of skeletal muscle size increases, it is vital to gain a full understanding of the role that Myostatin plays during prenatal life. This review brings together data from numerous animal models to establish the mechanisms of Myostatin action during embryonic and foetal development. We highlight the temporal and spatial control of Myostatin expression in a variety of vertebrate species and the mechanisms by which Myostatin gene expression is regulated. We draw attention to the key loss- and gain-of-function developmental experiments to formulate a model to explain how Myostatin acts to control skeletal muscle growth during development.

Hundreds of thousands of individuals suffer disability from skeletal muscle weakness associated with neuromuscular disease. Inhibition of the TGF-β family member, myostatin, may mitigate symptoms in these disorders regardless of the primary disease pathophysiology. There is substantial preclinical data that primary muscle disorders may benefit from myostatin inhibition. In particular, several mouse models of various muscular dystrophies have demonstrated amelioration of pathology and weakness with loss or inhibition of myostatin. There is also preclinical data that myostatin inhibition may increase muscle mass and strength in some denervating diseases. In addition to increasing the quantity of muscle, myostatin inhibition improves the quality of muscle by stimulating muscle regeneration and decreases muscle fibrosis in animal models. Clinical experience with myostatin inhibitors is still limited and the potential negative consequences of long term inhibition are unknown but may include replicative senescence of muscle progenitor cells, tendon shortening and off-target side effects. Clinical trials in disease populations as well as long term treatment studies in large animal models are now required to determine the appropriate clinical use of this novel therapeutic.

Myostatin is a member of the TGFbeta family which is known to promote muscle wasting. Reduction of function mutations in this signaling molecule results in increased muscle mass in many different species examined including mice and humans. Age-related sarcopenia results in loss of strength and is a major contributing factor to falls and loss of independence in the elderly. Studies in rodents have demonstrated a decrease in myostatin expression in skeletal muscle whereas in humans there appears to be an increase in myostatin expression with age. Myostatin knockout mice have been reported to be resistant to the development of age-related sarcopenia and in humans, myostatin polymorphisms have been correlated with changes in muscle mass in the elderly. Treatment with an inhibitory antibody to myostatin increases muscle mass and, in combination with exercise, improves physical performance and metabolic parameters in aged mice and inhibition of myostatin pathway signaling with a dominant negative protein in aged mice speeds muscle regeneration after injury. Studies in old mice and rats suggest inhibition or loss of myostatin improves key features of skeletal muscle organization which are compromised in age-related sarcopenia and understanding the role of myostatin in aging skeletal muscle may reveal potential novel therapies for this unmet medical need.

Myostatin is a member of the transforming growth factor β superfamily of secreted growth factors that negatively regulates skeletal muscle size. Mice null for the myostatin gene have a dramatically increased mass of individual muscles, reduced adiposity, increased insulin sensitivity, and resistance to obesity. Myostatin inhibition in adult mice also increases muscle mass which raises the possibility that anti-myostatin therapy could be a useful approach for treating diseases such as obesity or diabetes in addition to muscle wasting diseases. In this review I will describe the present state of our understanding of the role of myostatin and the closely related growth factor growth/differentiation factor 11 on metabolism.

Age-associated loss of skeletal muscle mass and strength, termed sarcopenia, is a major public health concern. Individuals with sarcopenia and frailty have decreased physical function and are at increased risk of cardiovascular and metabolic disorders. Despite the remarkable gains in the human health span, cardiometabolic disorders remain the leading cause of mortality worldwide. Here, we discuss the potential therapeutic implications of promyogenic function promoting anabolic agents, particularly myostatin antagonists, in the prevention of a variety of age-related metabolic disorders.

Increasing muscle mass is one of the primary breeding objectives in domestic animals as it translates in enhanced carcass yield in livestock or improved athletic performances in companion animals. Naturally occurring loss-offunction mutations in the MSTN gene have been shown to underlie the “double-muscling” phenotype in cattle, the “increased muscle mass” phenotype in sheep and the “bully” phenotype in sprinter dogs. Hypomorphic MSTN alleles associated with weaker but sometimes more advantageous effects on muscle mass have been identified in cattle and sheep. MSTN is a prime target for transgenic approaches aimed at enhancing meat production in livestock. Strategies that are being explored include the generation of MSTN “knock-out” animals and the expression in skeletal muscle of MSTN transinhibitors. More elaborate transgenic approaches targeting post-natal or sex-specific inhibition of MSTN are also being pursued. Finally, MSTN is an obvious target for pharmacological inhibition as well as immunomodulation with the aim to increase muscle mass in animals.

Lipoprotein related protein (LRP)-2 is a class of single transmembrane glycoprotein, generally recognized as cell surface endocytic receptors, which binds and internalizes extracellular ligands for degradation in lysosomes. LRP-2 is a multi-ligand endocytic receptor expressed in the choroid plexus epithelium, brain-endothelial cells, astrocytes, spinal cord, and retinal ganglion cells, and widely distributed in neurons through the brain. In the blood-brain-barrier LRP-2 plays a central role in the clearance/entrance of many proteins from the brain/cerebrospinal fluid. It has already been implicated in amyloid-β clearance and amyloidosis through the blood brain barrier. Also, it is a promiscuous receptor involved in the endocytic uptake of dozens of ligands, including many of the known carriers of amyloid-beta, insulin, insulin-like growth factor (IGF)-I, leptin, transthyretin, transferrin, apolipoprotein E (ApoE) and other molecules regulating the environment of the brain. LRP-2 immunoreactivity was also localized in neurons in different stages, suggesting that LRP-2 is implicated in signal transduction during embryonic development, neuronal outgrowth or in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease. Recently, information regarding the structural and functional elements within their cytoplasmic tail has begun to emerge, which suggests that LRP-2 is working not only in receptor mediated endocytosis, but also in transducing signals into the cytoplasm. It was reported that LRP-2 is subjected to regulated intramembrane proteolysis producing a soluble extracellular fragment and LRP-2 intracellular domain (ICD-LRP-2). Based on similar studies with other receptors, the ICD-LRP-2 is predicted to target to the nucleus and regulate gene expression. These findings suggest that LRP-2 has a crucial role in development of central nervous system, regulation of transcription factors, neuronal outgrowth and regulation of signal transducing pathways in the neuron. This review will discuss the new facts about the knowledge of LRP-2 in the central nervous system in healthy and also different pathological situations.