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.

Intramuscular β2-agonist administration enhances early regeneration and functional repair in rat skeletal muscle after myotoxic injury

2008 ◽  
Vol 105 (1) ◽  
pp. 165-172 ◽  
Author(s):  
James G. Ryall ◽  
Jonathan D. Schertzer ◽  
Tammy M. Alabakis ◽  
Stefan M. Gehrig ◽  
David R. Plant ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Side Effects ◽  
Cardiac Hypertrophy ◽  
Muscle Mass ◽  
Intramuscular Injection ◽  
Therapeutic Potential ◽  
Cardiovascular Effects ◽  
Skeletal Muscle Regeneration ◽  
Cardiovascular Side Effects ◽  
The Right

Systemic administration of β2-adrenoceptor agonists (β2-agonists) can improve skeletal muscle regeneration after injury. However, therapeutic application of β2-agonists for muscle injury has been limited by detrimental cardiovascular side effects. Intramuscular administration may obviate some of these side effects. To test this hypothesis, the right extensor digitorum longus (EDL) muscle from rats was injected with bupivacaine hydrochloride to cause complete muscle fiber degeneration. Five days after injury, half of the injured muscles received an intramuscular injection of formoterol (100 μg). Muscle function was assessed at 7, 10, and 14 days after injury. A single intramuscular injection of formoterol increased muscle mass and force-producing capacity at day 7 by 17 and 91%, respectively, but this effect was transient because these values were not different from control levels at day 10. A second intramuscular injection of formoterol at day 7 prolonged the increase in muscle mass and force-producing capacity. Importantly, single or multiple intramuscular injections of formoterol did not elicit cardiac hypertrophy. To characterize any potential cardiovascular effects of intramuscular formoterol administration, we instrumented a separate group of rats with indwelling radio telemeters. Following an intramuscular injection of formoterol, heart rate increased by 18%, whereas systolic and diastolic blood pressure decreased by 31 and 44%, respectively. These results indicate that intramuscular injection can enhance functional muscle recovery after injury without causing cardiac hypertrophy. Therefore, if the transient cardiovascular effects associated with intramuscular formoterol administration can be minimized, this form of treatment may have significant therapeutic potential for muscle-wasting conditions.

scholarly journals The bone morphogenetic protein axis is a positive regulator of skeletal muscle mass

2013 ◽  
Vol 203 (2) ◽  
pp. 345-357 ◽  
Author(s):  
Catherine E. Winbanks ◽  
Justin L. Chen ◽  
Hongwei Qian ◽  
Yingying Liu ◽  
Bianca C. Bernardo ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Bone Morphogenetic Protein ◽  
Signaling Pathway ◽  
Muscle Mass ◽  
Muscle Wasting ◽  
Muscle Growth ◽  
Bmp Signaling ◽  
Positive Regulator ◽  
Bmp Receptors ◽  
Morphogenetic Protein

Although the canonical transforming growth factor β signaling pathway represses skeletal muscle growth and promotes muscle wasting, a role in muscle for the parallel bone morphogenetic protein (BMP) signaling pathway has not been defined. We report, for the first time, that the BMP pathway is a positive regulator of muscle mass. Increasing the expression of BMP7 or the activity of BMP receptors in muscles induced hypertrophy that was dependent on Smad1/5-mediated activation of mTOR signaling. In agreement, we observed that BMP signaling is augmented in models of muscle growth. Importantly, stimulation of BMP signaling is essential for conservation of muscle mass after disruption of the neuromuscular junction. Inhibiting the phosphorylation of Smad1/5 exacerbated denervation-induced muscle atrophy via an HDAC4-myogenin–dependent process, whereas increased BMP–Smad1/5 activity protected muscles from denervation-induced wasting. Our studies highlight a novel role for the BMP signaling pathway in promoting muscle growth and inhibiting muscle wasting, which may have significant implications for the development of therapeutics for neuromuscular disorders.

scholarly journals Inhibition of Activin/Myostatin signalling induces skeletal muscle hypertrophy but impairs mouse testicular development

2020 ◽  
Vol 30 (1) ◽  
pp. 62-78
Author(s):  
Danielle Vaughan ◽  
Olli Ritvos ◽  
Robert Mitchell ◽  
Oliver Kretz ◽  
Maciej Lalowski ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Therapeutic Strategy ◽  
Cancer Cachexia ◽  
Muscle Growth ◽  
Neuromuscular Diseases ◽  
Testicular Development ◽  
Testicular Seminoma ◽  
Skeletal Muscle Hypertrophy ◽  
Similar Mode ◽  
Model Treatment

Numerous approaches are being developed to promote post-natal muscle growth based on attenuating Myostatin/Activin signalling for clinical uses such as the treatment neuromuscular diseases, cancer cachexia and sarcopenia. However there have been concerns about the effects of inhibiting Activin on tissues other than skeletal muscle. We intraperitoneally injected mice with the Activin ligand trap, sActRIIB, in young, adult and a progeric mouse model. Treatment at any stage in the life of the mouse rapidly increased muscle mass. However at all stages of life the treatment decreased the weights of the testis. Not only were the testis smaller, but they contained fewer sperm compared to untreated mice. We found that the hypertrophic muscle phenotype was lost after the cessation of sActRIIB treatment but abnormal testis phenotype persisted. In summary, attenuation of Myostatin/Activin signalling inhibited testis development. Future use of molecules based on a similar mode of action to promote muscle growth should be carefully profiled for adverse side-effects on the testis. However the effectiveness of sActRIIB as a modulator of Activin function provides a possible therapeutic strategy to alleviate testicular seminoma development.

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.

Beneficial Effects of Skeletal Muscle Growth on Cardiovascular Diseases

2013 ◽  
Vol 19 (10) ◽  
pp. S123
Author(s):  
Yasuhiro Izumiya ◽  
Satoshi Araki ◽  
Shinsuke Hanatani ◽  
Hisao Ogawa
Keyword(s):  
Skeletal Muscle ◽  
Cardiovascular Diseases ◽  
Muscle Growth ◽  
Skeletal Muscle Growth ◽  
Beneficial Effects

scholarly journals Effects of β2-agonist administration and exercise on contractile activation of skeletal muscle fibers

1996 ◽  
Vol 81 (4) ◽  
pp. 1610-1618 ◽  
Author(s):  
Gordon S. Lynch ◽  
Alan Hayes ◽  
Siun P. Campbell ◽  
David A. Williams
Keyword(s):  
Skeletal Muscle ◽  
Muscle Wasting ◽  
Therapeutic Potential ◽  
Fiber Type ◽  
Muscle Fibers ◽  
Low Intensity ◽  
Skeletal Muscle Fibers ◽  
Contractile Activation ◽  
Low Intensity Exercise ◽  
And Control

Lynch, Gordon S., Alan Hayes, Siun P. Campbell, and David A. Williams. Effects of β2-agonist administration and exercise on contractile activation of skeletal muscle fibers. J. Appl. Physiol. 81(4): 1610–1618, 1996.—Clenbuterol, a β2-adrenoceptor agonist, has therapeutic potential for the treatment of muscle-wasting diseases, yet its effects, especially at the single-fiber level, have not been fully characterized. Male C57BL/10 mice were allocated to three groups: Control-Treated mice were administered clenbuterol (2 mg ⋅ kg−1 ⋅ day−1) via their drinking water for 15 wk; Trained-Treated mice underwent low-intensity training (unweighted swimming, 5 days/wk, 1 h/day) in addition to receiving clenbuterol; and Control mice were sedentary and untreated. Contractile characteristics were determined on membrane-permeabilized fibers from the extensor digitorum longus (EDL) and soleus muscles. Fast fibers from the EDL and soleus muscles of Treated mice exhibited decreases in Ca2+ sensitivity. Endurance exercise offset clenbuterol’s effects, demonstrated by similar Ca2+ sensitivities in the Trained-Treated and Control groups. Long-term clenbuterol treatment did not affect the normalized maximal tension of fast or slow fibers but increased the proportion of fast fibers in the soleus muscle. Training increased the proportion of fibers with high and intermediate succinate dehydrogenase activity in the EDL and soleus muscles, respectively. If clenbuterol is to be used for treating muscle-wasting disorders, some form of low-intensity exercise might be encouraged such that potentially deleterious slow-to-fast fiber type transformations are minimized. Indeed, in the mouse, low-intensity exercise appears to prevent these effects.

scholarly journals The mechanisms of muscle wasting in COPD and heart failure

2012 ◽  
Author(s):  
Giorgio Vescovo
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Growth Hormone ◽  
Growth Factor ◽  
Ubiquitin Ligase ◽  
Muscle Wasting ◽  
The Body ◽  
Adrenergic System ◽  
Muscle Dysfunction ◽  
Insulin Like Growth Factor

Many of the mechanisms leading to skeletal muscle wasting in COPD and heart failure are common to both conditions. These encompass neurohormonal activation and systemic inflammation. The mechanisms leading to muscle dysfunction are both qualitative and quantitative. Qualitative changes comprise the transition from aerobic metabolism and prevalent slow fibers composition toward anaerobic metabolism and fast fibers synthesis. Quantitative changes are mainly linked to muscle loss. These changes occur not only in the major muscles bulks of the body but also in respiratory muscles. The mechanisms leading to muscle wastage include cytokine-triggered skeletal muscle apoptosis and ubiquitin-proteasomeand non-ubiquitin-dependent pathways. The regulation of fiber type involves the growth hormone/insulin-like growth factor 1/calcineurin/transcriptional coactivator PGC1 cascade. The imbalance between protein synthesis and degradation plays an important role. Protein degradation can occur through ubiquitin-dependent and non-ubiquitin-dependent pathways. Very recently, two systems controlling ubiquitin-proteasome activation have been described: FOXO-ubiquitin ligase and NFkB ubiquitin ligase. These are triggered by TNFα and growth hormone/insulin-like growth factor 1. Moreover, apoptosis, which is triggered by tumor necrosis factor α, plays an important role. Another mechanism acting on muscle wastage is malnutrition, with an imbalance between catabolic and anabolic factors toward the catabolic component. Catabolism is also worsened by the activation of the adrenergic system and alteration of the cortisol/DEHA ratio toward cortisol production. Sarcomeric protein oxidation and its consequent contractile impairment can be another cause of skeletal muscle dysfunction in CHF.

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.

scholarly journals Inhibition of HSP90 reversed STAT3 mediated muscle wasting induced by cancer cachexia

2021 ◽  
Author(s):  
Mengyuan Niu ◽  
Shiyu Song ◽  
Zhonglan Su ◽  
Lulu Wei ◽  
Li Li ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cancer Cachexia ◽  
Molecular Mechanisms ◽  
Muscle Wasting ◽  
Therapeutic Potential ◽  
Mechanistic Study ◽  
Dependent Manner ◽  
Mice Model ◽  
Common Causes

AbstractCancer cachexia is one of the most common causes of death among cancer patients, no effective anti-cachectic treatment is currently available. In experimental cachectic models, aberrant activation of STAT3 in skeletal muscle has been found to contribute to muscle wasting. However, its clinical association, the factors regulating STAT3 activation, and the molecular mechanisms of STAT3-induced muscle atrophy in cancer cachexia remain incompletely understood. Here, we show that an enhanced interaction between STAT3 and HSP90, which causes the persistent STAT3 activation in the skeletal muscle of cancer cachexia patients, is the crucial event for the development of cachectic muscle wasting. Administration of HSP90 inhibitors alleviated the muscle wasting in C26 tumor-bearing cachetic mice model or C26 conditional medium induced C2C12 myotube atrophy. A mechanistic study indicated that in cachectic skeletal muscle, prolonged STAT3 activation triggered muscle wasting in a FOXO1-dependent manner, STAT3 activated FOXO1 by binding directly to its promoter. Our results provide key insights into the role of the HSP90/STAT3/FOXO1 axis in cachectic muscle wasting, which shows promising therapeutic potential as a target for the treatment of cancer cachexia.

scholarly journals Myostatin from the heart: local and systemic actions in cardiac failure and muscle wasting

2011 ◽  
Vol 300 (6) ◽  
pp. H1973-H1982 ◽  
Author(s):  
Astrid Breitbart ◽  
Mannix Auger-Messier ◽  
Jeffery D. Molkentin ◽  
Joerg Heineke
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Muscle Wasting ◽  
Muscle Growth ◽  
Skeletal Muscle Atrophy ◽  
Cardiac Cachexia ◽  
Heart Failure Patients ◽  
Skeletal Muscle Growth ◽  
Skeletal Muscle Wasting

A significant proportion of heart failure patients develop skeletal muscle wasting and cardiac cachexia, which is associated with a very poor prognosis. Recently, myostatin, a cytokine from the transforming growth factor-β (TGF-β) family and a known strong inhibitor of skeletal muscle growth, has been identified as a direct mediator of skeletal muscle atrophy in mice with heart failure. Myostatin is mainly expressed in skeletal muscle, although basal expression is also detectable in heart and adipose tissue. During pathological loading of the heart, the myocardium produces and secretes myostatin into the circulation where it inhibits skeletal muscle growth. Thus, genetic elimination of myostatin from the heart reduces skeletal muscle atrophy in mice with heart failure, whereas transgenic overexpression of myostatin in the heart is capable of inducing muscle wasting. In addition to its endocrine action on skeletal muscle, cardiac myostatin production also modestly inhibits cardiomyocyte growth under certain circumstances, as well as induces cardiac fibrosis and alterations in ventricular function. Interestingly, heart failure patients show elevated myostatin levels in their serum. To therapeutically influence skeletal muscle wasting, direct inhibition of myostatin was shown to positively impact skeletal muscle mass in heart failure, suggesting a promising strategy for the treatment of cardiac cachexia in the future.

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