scholarly journals Myostatin/Activin Receptor Ligands In Muscle And The Development Status Of Attenuating Drugs

2021 ◽  
Author(s):  
Buel D Rodgers ◽  
Christopher W Ward
Keyword(s):  
Muscle Function ◽  
Muscle Wasting ◽  
Metabolic Diseases ◽  
Muscle Growth ◽  
Neuromuscular Diseases ◽  
Treatment Strategies ◽  
Noncommunicable Disease ◽  
Cell Protein ◽  
Renal Diseases ◽  
Activin Receptor

Abstract Muscle wasting disease indications are among the most debilitating and often deadly noncommunicable disease states. As a comorbidity, muscle wasting is associated with different neuromuscular diseases and myopathies, cancer, heart failure, chronic pulmonary and renal diseases, peripheral neuropathies, inflammatory disorders and of course, musculoskeletal injuries. Current treatment strategies are relatively ineffective and can at best only limit the rate of muscle degeneration. This includes nutritional supplementation and appetite stimulants as well as immunosuppressants capable of exacerbating muscle loss. Arguably, the most promising treatments in development attempt to disrupt myostatin and activin receptor signaling as these circulating factors are potent inhibitors of muscle growth and regulators of muscle progenitor cell differentiation. Indeed, several studies demonstrated the clinical potential of “inhibiting the inhibitors”, increasing muscle cell protein synthesis, decreasing degradation, enhancing mitochondrial biogenesis and preserving muscle function. Such changes can prevent muscle wasting in various disease animal models yet many drugs targeting this pathway failed during clinical trials, some from serious treatment-related adverse events and off-target interactions. More often, however, failures resulted from the inability to improve muscle function despite preserving muscle mass. Drugs still in development include antibodies and gene therapeutics, all with different targets and thus, safety, efficacy and proposed use profiles. Each is unique in design and, if successful, could revolutionize the treatment of both acute and chronic muscle wasting. They could also be used in combination with other developing therapeutics for related muscle pathologies or even metabolic diseases.

Signaling in Muscle Atrophy and Hypertrophy

Physiology ◽  
2008 ◽  
Vol 23 (3) ◽  
pp. 160-170 ◽  
Author(s):  
Marco Sandri
Keyword(s):  
Physical Activity ◽  
Protein Synthesis ◽  
Growth Factors ◽  
Muscle Atrophy ◽  
Muscle Wasting ◽  
Muscle Growth ◽  
Neuromuscular Diseases ◽  
Muscle Performance ◽  
Prevention And Treatment ◽  
Atrophy And Hypertrophy

Muscle performance is influenced by turnover of contractile proteins. Production of new myofibrils and degradation of existing proteins is a delicate balance, which, depending on the condition, can promote muscle growth or loss. Protein synthesis and protein degradation are coordinately regulated by pathways that are influenced by mechanical stress, physical activity, availability of nutrients, and growth factors. Understanding the signaling that regulates muscle mass may provide potential therapeutic targets for the prevention and treatment of muscle wasting in metabolic and neuromuscular diseases.

Role of β-Adrenoceptor Signaling in Skeletal Muscle: Implications for Muscle Wasting and Disease

2008 ◽  
Vol 88 (2) ◽  
pp. 729-767 ◽  
Author(s):  
Gordon S. Lynch ◽  
James G. Ryall
Keyword(s):  
Skeletal Muscle ◽  
Muscle Wasting ◽  
Therapeutic Potential ◽  
Muscle Growth ◽  
Neuromuscular Diseases ◽  
Cardiovascular Effects ◽  
Adrenergic System ◽  
Adrenergic Signaling ◽  
Beneficial Effects ◽  
Cardiovascular Side Effects

The importance of β-adrenergic signaling in the heart has been well documented, but it is only more recently that we have begun to understand the importance of this signaling pathway in skeletal muscle. There is considerable evidence regarding the stimulation of the β-adrenergic system with β-adrenoceptor agonists (β-agonists). Although traditionally used for treating bronchospasm, it became apparent that some β-agonists could increase skeletal muscle mass and decrease body fat. These so-called “repartitioning effects” proved desirable for the livestock industry trying to improve feed efficiency and meat quality. Studying β-agonist effects on skeletal muscle has identified potential therapeutic applications for muscle wasting conditions such as sarcopenia, cancer cachexia, denervation, and neuromuscular diseases, aiming to attenuate (or potentially reverse) the muscle wasting and associated muscle weakness, and to enhance muscle growth and repair after injury. Some undesirable cardiovascular side effects of β-agonists have so far limited their therapeutic potential. This review describes the physiological significance of β-adrenergic signaling in skeletal muscle and examines the effects of β-agonists on skeletal muscle structure and function. In addition, we examine the proposed beneficial effects of β-agonist administration on skeletal muscle along with some of the less desirable cardiovascular effects. Understanding β-adrenergic signaling in skeletal muscle is important for identifying new therapeutic targets and identifying novel approaches to attenuate the muscle wasting concomitant with many diseases.

scholarly journals Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD)—A Condition Associated with Heightened Sympathetic Activation

2021 ◽  
Vol 22 (8) ◽  
pp. 4241
Author(s):  
Revathy Carnagarin ◽  
Kearney Tan ◽  
Leon Adams ◽  
Vance B. Matthews ◽  
Marcio G. Kiuchi ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Metabolic Diseases ◽  
Treatment Strategies ◽  
Adverse Outcomes ◽  
Metabolic Dysfunction ◽  
Sympathetic Activation ◽  
Beneficial Effects ◽  
Adverse Health Outcomes

Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common liver disease affecting a quarter of the global population and is often associated with adverse health outcomes. The increasing prevalence of MAFLD occurs in parallel to that of metabolic syndrome (MetS), which in fact plays a major role in driving the perturbations of cardiometabolic homeostasis. However, the mechanisms underpinning the pathogenesis of MAFLD are incompletely understood. Compelling evidence from animal and human studies suggest that heightened activation of the sympathetic nervous system is a key contributor to the development of MAFLD. Indeed, common treatment strategies for metabolic diseases such as diet and exercise to induce weight loss have been shown to exert their beneficial effects at least in part through the associated sympathetic inhibition. Furthermore, pharmacological and device-based approaches to reduce sympathetic activation have been demonstrated to improve the metabolic alterations frequently present in patients with obesity, MetSand diabetes. Currently available evidence, while still limited, suggests that sympathetic activation is of specific relevance in the pathogenesis of MAFLD and consequentially may offer an attractive therapeutic target to attenuate the adverse outcomes associated with MAFLD.

scholarly journals Sustained Systemic Levels of IL-6 Impinge Early Muscle Growth and Induce Muscle Atrophy and Wasting in Adulthood

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1816
Author(s):  
Laura Pelosi ◽  
Maria Grazia Berardinelli ◽  
Laura Forcina ◽  
Francesca Ascenzi ◽  
Emanuele Rizzuto ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Muscle Wasting ◽  
Inflammatory Diseases ◽  
Early Stage ◽  
Muscle Growth ◽  
Postnatal Life ◽  
Stunted Growth ◽  
Skeletal Muscle Wasting ◽  
Potential Biomarker ◽  
Muscle Homeostasis

IL-6 is a pleiotropic cytokine that can exert different and opposite effects. The muscle-induced and transient expression of IL-6 can act in an autocrine or paracrine manner, stimulating anabolic pathways associated with muscle growth, myogenesis, and with regulation of energy metabolism. In contrast, under pathologic conditions, including muscular dystrophy, cancer associated cachexia, aging, chronic inflammatory diseases, and other pathologies, the plasma levels of IL-6 significantly increase, promoting muscle wasting. Nevertheless, the specific physio-pathological role exerted by IL-6 in the maintenance of differentiated phenotype remains to be addressed. The purpose of this study was to define the role of increased plasma levels of IL-6 on muscle homeostasis and the mechanisms contributing to muscle loss. Here, we reported that increased plasma levels of IL-6 promote alteration in muscle growth at early stage of postnatal life and induce muscle wasting by triggering a shift of the slow-twitch fibers toward a more sensitive fast fiber phenotype. These findings unveil a role for IL-6 as a potential biomarker of stunted growth and skeletal muscle wasting.

O.10 Effect of combined treatment with soluble activin receptor IIB and AAV-U7-mediated dystrophin exon skipping on muscle function in mdx mice

2011 ◽  
Vol 21 (9-10) ◽  
pp. 703
Author(s):  
W.M.H. Hoogaars ◽  
E. Mouisel ◽  
K. Relizani ◽  
A. Pasternack ◽  
C. Hourde ◽  
...  
Keyword(s):  
Muscle Function ◽  
Combined Treatment ◽  
Exon Skipping ◽  
Mdx Mice ◽  
Activin Receptor ◽  
Activin Receptor Iib ◽  
O 10

Mechanisms involved in developmental programming of hypertension and renal diseases. Gender differences

2014 ◽  
Vol 18 (2) ◽  
Author(s):  
Analia Lorena Tomat ◽  
Francisco Javier Salazar
Keyword(s):  
Metabolic Diseases ◽  
Current Knowledge ◽  
Adult Life ◽  
Developmental Programming ◽  
Renal Diseases ◽  
Future Studies ◽  
Functional Changes ◽  
Regulatory Systems ◽  
Increased Risk ◽  
Renal Changes

AbstractA substantial body of epidemiological and experimental evidence suggests that a poor fetal and neonatal environment may “program” susceptibility in the offspring to later development of cardiovascular, renal and metabolic diseases.This review focuses on current knowledge from the available literature regarding the mechanisms linking an adverse developmental environment with an increased risk for cardiovascular, renal and metabolic diseases in adult life. Moreover, this review highlights important sex-dependent differences in the adaptation to developmental insults.Developmental programming of several diseases is secondary to changes in different mechanisms inducing important alterations in the normal development of several organs that lead to significant changes in birth weight. The different diseases occurring as a consequence of an adverse environment during development are secondary to morphological and functional cardiovascular and renal changes, to epigenetic changes and to an activation of several hormonal and regulatory systems, such as angiotensin II, sympathetic activity, nitric oxide, COX2-derived metabolites, oxidative stress and inflammation. The important sex-dependent differences in the developmental programming of diseases seem to be partly secondary to the effects of sex hormones. Recent studies have shown that the progression of these diseases is accelerated during aging in both sexes.The cardiovascular, renal and metabolic diseases during adult life that occur as a consequence of several insults during fetal and postnatal periods are secondary to multiple structural and functional changes. Future studies are needed in order to prevent the origin and reduce the incidence and consequences of developmental programmed diseases.

scholarly journals Myostatin: genetic variants, therapy and gene doping

2012 ◽  
Vol 48 (3) ◽  
pp. 369-377 ◽  
Author(s):  
André Katayama Yamada ◽  
Rozangela Verlengia ◽  
Carlos Roberto Bueno Junior
Keyword(s):  
Athletic Performance ◽  
Genetic Variants ◽  
Muscle Hypertrophy ◽  
Muscle Wasting ◽  
Genetic Manipulation ◽  
Muscle Growth ◽  
Gene Doping ◽  
Oxidative Phenotype ◽  
Illicit Use ◽  
Myoblast Transplantation

Since its discovery, myostatin (MSTN) has been at the forefront of muscle therapy research because intrinsic mutations or inhibition of this protein, by either pharmacological or genetic means, result in muscle hypertrophy and hyperplasia. In addition to muscle growth, MSTN inhibition potentially disturbs connective tissue, leads to strength modulation, facilitates myoblast transplantation, promotes tissue regeneration, induces adipose tissue thermogenesis and increases muscle oxidative phenotype. It is also known that current advances in gene therapy have an impact on sports because of the illicit use of such methods. However, the adverse effects of these methods, their impact on athletic performance in humans and the means of detecting gene doping are as yet unknown. The aim of the present review is to discuss biosynthesis, genetic variants, pharmacological/genetic manipulation, doping and athletic performance in relation to the MSTN pathway. As will be concluded from the manuscript, MSTN emerges as a promising molecule for combating muscle wasting diseases and for triggering wide-ranging discussion in view of its possible use in gene doping.

Adverse effects of myasthenia gravis on rat phrenic diaphragm contractile performance

2004 ◽  
Vol 97 (3) ◽  
pp. 895-901 ◽  
Author(s):  
Erik van Lunteren ◽  
Michelle Moyer ◽  
Henry J. Kaminski
Keyword(s):  
Myasthenia Gravis ◽  
Muscle Function ◽  
Initial Period ◽  
Neuromuscular Diseases ◽  
Diaphragm Muscle ◽  
Twitch Force ◽  
Continuous Stimulation ◽  
Intermittent Stimulation ◽  
Contractile Performance

Myasthenia gravis has variable effects on the respiratory system, ranging from no abnormalities to life-threatening respiratory failure. Studies characterized diaphragm muscle contractile performance in rat autoimmune myasthenia gravis. Rats received monoclonal antibody that recognizes acetylcholine receptor determinants (or inactive antibody); 3 days later, phrenic nerve and diaphragm were studied in vitro. Myasthenic rats segregated into two groups, those with normal vs. impaired limb muscle function when tested in intact animals (“mild” and “severe” myasthenic). Baseline diaphragm twitch force was reduced for both severe ( P < 0.01) and mild ( P < 0.05) myasthenic compared with control animals (twitch force: normal 1,352 ± 140, mild myasthenic 672 ± 99, severe myasthenic 687 ± 74 g/cm2). However, only severe myasthenic diaphragm had impaired diaphragm endurance, based on significantly ( P < 0.05) accelerated rate of peak force decline during the initial period of stimulation (0.02 + 0.02, 0.03 ± 0.01, and 0.09 ± 0.01%/pulse for normal, mild myasthenic, and severe myasthenic, respectively, during continuous stimulation) and intratrain fatigue (up to 30.5 ± 7.4% intratrain force drop in severe myasthenic vs. none in normal and mild myasthenic, P < 0.01). Furthermore, compared with continuous stimulation, intermittent stimulation had a protective effect on force of severe myasthenic diaphragm (force after 2,000 pulses was 31.4 ± 2.0% of initial during intermittent stimulation vs. 13.0 ± 2.1% of initial during continuous stimulation, P < 0.01) but not on normal diaphragm. These data indicate that baseline force and fatigue may be affected to different extents by varying severity of myasthenia gravis and furthermore provide a mechanism by which alterations in breathing pattern may worsen respiratory muscle function in neuromuscular diseases.

scholarly journals How to Steer and Control ERK and the ERK Signaling Cascade Exemplified by Looking at Cardiac Insufficiency

2019 ◽  
Vol 20 (9) ◽  
pp. 2179
Author(s):  
Tim Breitenbach ◽  
Kristina Lorenz ◽  
Thomas Dandekar
Keyword(s):  
Drug Targets ◽  
Muscle Growth ◽  
Treatment Strategies ◽  
Mathematical Optimization ◽  
Activity Level ◽  
Cardiac Insufficiency ◽  
Pharmacological Intervention ◽  
Beneficial Effects ◽  
Optimal Drug ◽  
Automatic Search

Mathematical optimization framework allows the identification of certain nodes within a signaling network. In this work, we analyzed the complex extracellular-signal-regulated kinase 1 and 2 (ERK1/2) cascade in cardiomyocytes using the framework to find efficient adjustment screws for this cascade that is important for cardiomyocyte survival and maladaptive heart muscle growth. We modeled optimal pharmacological intervention points that are beneficial for the heart, but avoid the occurrence of a maladaptive ERK1/2 modification, the autophosphorylation of ERK at threonine 188 (ERK Thr 188 phosphorylation), which causes cardiac hypertrophy. For this purpose, a network of a cardiomyocyte that was fitted to experimental data was equipped with external stimuli that model the pharmacological intervention points. Specifically, two situations were considered. In the first one, the cardiomyocyte was driven to a desired expression level with different treatment strategies. These strategies were quantified with respect to beneficial effects and maleficent side effects and then which one is the best treatment strategy was evaluated. In the second situation, it was shown how to model constitutively activated pathways and how to identify drug targets to obtain a desired activity level that is associated with a healthy state and in contrast to the maleficent expression pattern caused by the constitutively activated pathway. An implementation of the algorithms used for the calculations is also presented in this paper, which simplifies the application of the presented framework for drug targeting, optimal drug combinations and the systematic and automatic search for pharmacological intervention points. The codes were designed such that they can be combined with any mathematical model given by ordinary differential equations.

Role of sepsis in the development of limb muscle weakness in a porcine intensive care unit model

2012 ◽  
Vol 44 (18) ◽  
pp. 865-877 ◽  
Author(s):  
Sudhakar Aare ◽  
Peter Radell ◽  
Lars I. Eriksson ◽  
Yi-Wen Chen ◽  
Eric P. Hoffman ◽  
...  
Keyword(s):  
Intensive Care Unit ◽  
Intensive Care ◽  
Heat Shock ◽  
Critically Ill ◽  
Muscle Function ◽  
Muscle Wasting ◽  
Limb Muscle ◽  
Negative Consequences ◽  
Icu Patients ◽  
Biceps Femoris Muscle

Severe muscle wasting and loss of muscle function in critically ill mechanically ventilated intensive care unit (ICU) patients have significant negative consequences on their recovery and rehabilitation that persist long after their hospital discharge; moreover, the underlying mechanisms are unclear. Mechanical ventilation (MV) and immobilization-induced modifications play an important role in these consequences, including endotoxin-induced sepsis. The present study aims to investigate how sepsis aggravates ventilator and immobilization-related limb muscle dysfunction. Hence, biceps femoris muscle gene expression was investigated in pigs exposed to ICU intervention, i.e., immobilization, sedation, and MV, alone or in combination with sepsis, for 5 days. In previous studies, we have shown that ICU intervention alone or in combination with sepsis did not affect muscle fiber size on day 5, but a significant decrease was observed in single fiber maximal force normalized to cross-sectional area (specific force) when sepsis was added to the ICU intervention. According to microarray data, the addition of sepsis to the ICU intervention induced a deregulation of >500 genes, such as an increased expression of genes involved in chemokine activity, kinase activity, and transcriptional regulation. Genes involved in the regulation of the oxidative stress response and cytoskeletal/sarcomeric and heat shock proteins were on the other hand downregulated when sepsis was added to the ICU intervention. Thus, sepsis has a significant negative effect on muscle function in critically ill ICU patients, and chemokine activity and heat shock protein genes are forwarded to play an instrumental role in this specific muscle wasting condition.

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