Progression Of Muscle Wasting Research Articles

Targeting Epigenetic Regulators with HDAC and BET Inhibitors to Modulate Muscle Wasting.

Epigenetic changes contribute to the profound alteration in the transcriptional program associated with the onset and progression of muscle wasting in several pathological conditions. Although HDACs and their inhibitors have been extensively studied in the field of muscular dystrophies, the potential of epigenetic inhibitors has only been marginally explored in other disorders associated with muscle atrophy, such as in cancer cachexia and sarcopenia. BET inhibitors represent a novel class of recently developed epigenetic drugs that display beneficial effects in a variety of diseases beyond malignancies. Based on the preliminary in vitro and preclinical data, HDACs and BET proteins contribute to the pathogenesis of cancer cachexia and sarcopenia, modulating processes related to skeletal muscle mass maintenance and/or metabolism. Thus, epigenetic drugs targeting HDACs and BET proteins may emerge as promising strategies to reverse the catabolic phenotype associated with cachexia and sarcopenia. Further preclinical studies are warranted to delve deeper into the molecular mechanisms associated with the functions of HDACs and BET proteins in muscle atrophy and to establish whether their epigenetic inhibitors represent a prospective therapeutic avenue to alleviate muscle wasting.

The role of extracellular vesicles in skeletal muscle wasting.

Skeletal muscle wasting is a complicated metabolic syndrome accompanied by multiple diseases ranging from cancer to metabolic disorders and infectious conditions. The loss of muscle mass significantly impairs muscle function, resulting in poor quality of life and high mortality of associated diseases. The fundamental cellular and molecular mechanisms inducing muscle wasting have been well established, and those related pathways can be activated by a variety of extracellular signals, including inflammatory cytokines and catabolic stimuli. As an emerging messenger of cell-to-cell communications, extracellular vesicles (EVs) also get involved in the progression of muscle wasting by transferring bioactive cargoes including various proteins and non-coding RNAs to skeletal muscle. Like a double-edged sword, EVs play either a pro-wasting or anti-wasting role in the progression of muscle wasting, highly dependent on their parental cells as well as the specific type of cargo they encapsulate. This review aims to illustrate the current knowledge about the biological function of EVs cargoes in skeletal muscle wasting. Additionally, the potential therapeutic implications of EVs in the diagnosis and treatment of skeletal muscle wasting are also discussed. Simultaneously, several outstanding questions are included to shed light on future research.

Shared and Divergent Epigenetic Mechanisms in Cachexia and Sarcopenia.

Significant loss of muscle mass may occur in cachexia and sarcopenia, which are major causes of mortality and disability. Cachexia represents a complex multi-organ syndrome associated with cancer and chronic diseases. It is often characterized by body weight loss, inflammation, and muscle and adipose wasting. Progressive muscle loss is also a hallmark of healthy aging, which is emerging worldwide as a main demographic trend. A great challenge for the health care systems is the age-related decline in functionality which threatens the independence and quality of life of elderly people. This biological decline can also be associated with functional muscle loss, known as sarcopenia. Previous studies have shown that microRNAs (miRNAs) play pivotal roles in the development and progression of muscle wasting in both cachexia and sarcopenia. These small non-coding RNAs, often carried in extracellular vesicles, inhibit translation by targeting messenger RNAs, therefore representing potent epigenetic modulators. The molecular mechanisms behind cachexia and sarcopenia, including the expression of specific miRNAs, share common and distinctive trends. The aim of the present review is to compile recent evidence about shared and divergent epigenetic mechanisms, particularly focusing on miRNAs, between cachexia and sarcopenia to understand a facet in the underlying muscle wasting associated with these morbidities and disclose potential therapeutic interventions.

Plant Bioactives in the Treatment of Inflammation of Skeletal Muscles: A Molecular Perspective.

Skeletal muscle mass responds rapidly to growth stimuli, precipitating hypertrophies (increased protein synthesis) and hyperplasia (activation of the myogenic program). For ages, muscle degeneration has been attributed to changes in the intracellular myofiber pathways. These pathways are tightly regulated by hormones and lymphokines that ultimately pave the way to decreased anabolism and accelerated protein breakdown. Despite the lacunae in our understanding of specific pathways, growing bodies of evidence suggest that the changes in the myogenic/regenerative program are the major contributing factor in the development and progression of muscle wasting. In addition, inflammation plays a key role in the pathophysiology of diseases linked to the failure of skeletal muscles. Chronic inflammation with elevated levels of inflammatory mediators has been observed in a spectrum of diseases, such as inflammatory myopathies and chronic obstructive pulmonary disease (COPD). Although the pathophysiology of these diseases varies greatly, they all demonstrate sarcopenia and dysregulated skeletal muscle physiology as common symptoms. Medicinal plants harbor potential novel chemical moieties for a plenitude of illnesses, and inflammation is no exception. However, despite the vast number of potential antiinflammatory compounds found in plant extracts and isolated components, the research on medicinal plants is highly daunting. This review aims to explore the various phytoconstituents employed in the treatment of inflammatory responses in skeletal muscles, while providing an in-depth molecular insight into the latter.

Cancer Takes a Toll on Skeletal Muscle by Releasing Heat Shock Proteins-An Emerging Mechanism of Cancer-Induced Cachexia.

Cancer-associated cachexia (cancer cachexia) is a major contributor to the modality and mortality of a wide variety of solid tumors. It is estimated that cachexia inflicts approximately ~60% of all cancer patients and is the immediate cause of ~30% of all cancer-related death. However, there is no established treatment of this disorder due to the poor understanding of its underlying etiology. The key manifestations of cancer cachexia are systemic inflammation and progressive loss of skeletal muscle mass and function (muscle wasting). A number of inflammatory cytokines and members of the TGFβ superfamily that promote muscle protein degradation have been implicated as mediators of muscle wasting. However, clinical trials targeting some of the identified mediators have not yielded satisfactory results. Thus, the root cause of the muscle wasting associated with cancer cachexia remains to be identified. This review focuses on recent progress of laboratory studies in the understanding of the molecular mechanisms of cancer cachexia that centers on the role of systemic activation of Toll-like receptor 4 (TLR4) by cancer-released Hsp70 and Hsp90 in the development and progression of muscle wasting, and the downstream signaling pathways that activate muscle protein degradation through the ubiquitin–proteasome and the autophagy–lysosome pathways in response to TLR4 activation. Verification of these findings in humans could lead to etiology-based therapies of cancer cachexia by targeting multiple steps in this signaling cascade.

The AMPK agonist 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), but not metformin, prevents inflammation-associated cachectic muscle wasting.

Activation of AMPK has been associated with pro‐atrophic signaling in muscle. However, AMPK also has anti‐inflammatory effects, suggesting that in cachexia, a syndrome of inflammatory‐driven muscle wasting, AMPK activation could be beneficial. Here we show that the AMPK agonist AICAR suppresses IFNγ/TNFα‐induced atrophy, while the mitochondrial inhibitor metformin does not. IFNγ/TNFα impair mitochondrial oxidative respiration in myotubes and promote a metabolic shift to aerobic glycolysis, similarly to metformin. In contrast, AICAR partially restored metabolic function. The effects of AICAR were prevented by the AMPK inhibitor Compound C and were reproduced with A‐769662, a specific AMPK activator. AICAR and A‐769662 co‐treatment was found to be synergistic, suggesting that the anti‐cachectic effects of these drugs are mediated through AMPK activation. AICAR spared muscle mass in mouse models of cancer and LPS induced atrophy. Together, our findings suggest a dual function for AMPK during inflammation‐driven atrophy, wherein it can play a protective role when activated exogenously early in disease progression, but may contribute to anabolic suppression and atrophy when activated later through mitochondrial dysfunction and subsequent metabolic stress.

Can muscle protein metabolism be specifically targeted by exercise training in COPD?

Patients with stable chronic obstructive pulmonary disease (COPD) frequently exhibit unintentional accentuated peripheral muscle loss and dysfunction. Skeletal muscle mass in these patients is a strong independent predictor of morbidity and mortality. Factors including protein anabolism/catabolism imbalance, hypoxia, physical inactivity, inflammation, and oxidative stress are involved in the initiation and progression of muscle wasting in these patients. Exercise training remains the most powerful intervention for reversing, in part, muscle wasting in COPD. Independently of the status of systemic or local muscle inflammation, rehabilitative exercise training induces up-regulation of key factors governing skeletal muscle hypertrophy and regeneration. However, COPD patients presenting similar degrees of lung dysfunction do not respond alike to a given rehabilitative exercise stimulus. In addition, a proportion of patients experience limited clinical outcomes, even when exercise training has been adequately performed. Consistently, several reports provide evidence that the muscles of COPD patients present training-induced myogenic activity limitation as exercise training induces a limited number of differentially expressed genes, which are mostly associated with protein degradation. This review summarises the nature of muscle adaptations induced by exercise training, promoted both by changes in the expression of contractile proteins and their function typically controlled by intracellular signalling and transcriptional responses. Rehabilitative exercise training in COPD patients stimulates skeletal muscle mechanosensitive signalling pathways for protein accretion and its regulation during muscle contraction. Exercise training also induces synthesis of myogenic proteins by which COPD skeletal muscle promotes hypertrophy leading to fusion of myogenic cells to the myofiber. Understanding of the biological mechanisms that regulate exercise training-induced muscle growth and regeneration is necessary for implementing therapeutic strategies specifically targeting myogenesis and hypertrophy in these patients.

Identification of exosomal muscle-specific miRNAs in serum of myotonic dystrophy patients relating to muscle disease progress.

Myotonic dystrophy type 1 (DM1) is the most common form of adult-onset muscular dystrophy, which is characterised by progressive muscle wasting and the discovery of reliable blood-based biomarkers could be useful for the disease progress monitoring. There have been some reports showing that the presence of specific miRNAs in blood correlates with DM1. In one of these, our group identified four muscle-specific miRNAs, miR-1, miR-133a, miR-133b and miR-206, which correlated with the progression of muscle wasting observed in DM1 patients. The levels of the four muscle-specific miRNAs were elevated in the serum of DM1 patients compared to healthy participants and were also elevated in the serum of progressive muscle wasting DM1 patients compared to disease-stable DM1 patients. The aim of this work was to characterise the ontology of these four muscle-specific miRNAs in the blood circulation of DM1 patients. Here we show that the four muscle-specific miRNAs are encapsulated within exosomes isolated from DM1 patients. Our results show for the first time, the presence of miRNAs encapsulated within exosomes in blood circulation of DM1 patients. More interestingly, the levels of the four exosomal muscle-specific miRNAs are associated with the progression of muscle wasting in DM1 patients. We propose that exosomal muscle-specific miRNAs may be useful molecular biomarkers for monitoring the progress of muscle wasting in DM1 patients. There has been a growing interest regarding the clinical applications of exosomes and their role in prognosis and therapy of various diseases and the above results contribute towards this way.

Interference with Ca2+-Dependent Proteolysis Does Not Alter the Course of Muscle Wasting in Experimental Cancer Cachexia.

Protein hypercatabolism significantly contributes to the onset and progression of muscle wasting in cancer cachexia. In this regard, a major role is played by the ATP-ubiquitin-proteasome-dependent pathway and by autophagy. However, little is known about the relevance of the Ca2+-dependent proteolytic system. Since previous results suggested that this pathway is activated in the skeletal muscle of tumor hosts, the present study was aimed to investigate whether inhibition of Ca2+-dependent proteases (calpains) may improve cancer-induced muscle wasting. Two experimental models of cancer cachexia were used, namely the AH-130 Yoshida hepatoma and the C26 colon carcinoma. The Ca2+-dependent proteolytic system was inhibited by treating the animals with dantrolene or by overexpressing in the muscle calpastatin, the physiologic inhibitor of Ca2+-dependent proteases. The results confirm that calpain-1 is overexpressed and calpastatin is reduced in the muscle of rats implanted with the AH-130 hepatoma, and show for the first time that the Ca2+-dependent proteolytic system is overactivated also in the C26-bearing mice. Yet, administration of dantrolene, an inhibitor of the Ca2+-dependent proteases, did not modify tumor-induced body weight loss and muscle wasting in the AH-130 hosts. Dantrolene was also unable to reduce the enhancement of protein degradation rates occurring in rats bearing the AH-130 hepatoma. Similarly, overexpression of calpastatin in the tibialis muscle of the C26 hosts did not improve muscle wasting at all. These observations suggest that inhibiting a single proteolytic system is not a good strategy to contrast cancer-induced muscle wasting. In this regard, a more general and integrated approach aimed at targeting the catabolic stimuli rather than the proteolytic activity of a single pathway would likely be the most appropriate therapeutic intervention.

Elevated Muscle-Specific miRNAs in Serum of Myotonic Dystrophy Patients Relate to Muscle Disease Progress.

The discovery of reliable and sensitive blood biomarkers is useful for the diagnosis, monitoring and potential future therapy of diseases. Recently, microRNAs (miRNAs) have been identified in blood circulation and might have the potential to be used as biomarkers for several diseases and clinical conditions. Myotonic Dystrophy type 1 (DM1) is the most common form of adult-onset muscular dystrophy primarily characterized by muscle myotonia, weakness and atrophy. Previous studies have shown an association between miRNAs and DM1 in muscle tissue and, recently, in plasma. The aim of this study was to detect and assess muscle-specific miRNAs as potential biomarkers of DM1 muscle wasting, an important parameter in the disease’s natural history. Disease stable or progressive DM1 patients with muscle weakness and wasting were recruited and enrolled in the study. RNA isolated from participants’ serum was used to assess miRNA levels. Results suggest that the levels of muscle-specific miRNAs are correlated with the progression of muscle wasting and weakness observed in the DM1 patients. Specifically, miR-1, miR-133a, miR133b and miR-206 serum levels were found elevated in DM1 patients with progressive muscle wasting compared to disease stable DM1 patients. Based on these results, we propose that muscle-specific miRNAs might be useful molecular biomarkers for monitoring the progress of muscle atrophy in DM1 patients.

Exon skipping and Duchenne muscular dystrophy: Hope, hype and how feasible?

Duchenne muscular dystrophy (DMD), the most common and serious form of childhood muscle wasting is generally caused by protein-truncating mutations in the large DMD gene. Specific removal of an exon from a defective DMD gene transcript has the potential to allow synthesis of a semi-functional dystrophin, thereby reducing the severity and presumably progression of muscle wasting. The efficacy of this treatment will vary greatly between the different mutations that preclude the synthesis of a functional dystrophin. Restoration of the reading frame from a large multi-exon genomic deletion, typically greater than 36 exons, may lead to synthesis of a protein with only partial function and limited clinical benefit, whereas excising a nonsense mutation in a redundant exon should generate a near normal dystrophin. A clinical trial has recently confirmed proof-of-principle that exclusion of Exon 51 from human dystrophin mRNAs, carrying frame-shifting deletions adjacent to this exon, results in dystrophin expression. No major side-effects after local administration of the antisense oligomer were reported. Additional trials are underway, targeting the same exon but using an oligomer of different backbone chemistry. If functional dystrophin synthesis is demonstrated, and safety issues are addressed, subsequent trials will involve systemic delivery. Great challenges are ahead, some technical; establishing an effective delivery regimen, some ethical; choosing subsequent targets for therapy, and others of an administrative and regulatory nature.

Regulation of Protein Catabolism by Muscle-Specific and Cytokine-Inducible Ubiquitin Ligase E3α-II during Cancer Cachexia

The progressive depletion of skeletal muscle is a hallmark of many types of advanced cancer and frequently is associated with debility, morbidity, and mortality. Muscle wasting is primarily mediated by the activation of the ubiquitin-proteasome system, which is responsible for degrading the bulk of intracellular proteins. E3 ubiquitin ligases control polyubiquitination, a rate-limiting step in the ubiquitin-proteasome system, but their direct involvement in muscle protein catabolism in cancer remains obscure. Here, we report the full-length cloning of E3alpha-II, a novel "N-end rule" ubiquitin ligase, and its functional involvement in cancer cachexia. E3alpha-II is highly enriched in skeletal muscle, and its expression is regulated by proinflammatory cytokines. In two different animal models of cancer cachexia, E3alpha-II was significantly induced at the onset and during the progression of muscle wasting. The E3alpha-II activation in skeletal muscle was accompanied by a sharp increase in protein ubiquitination, which could be blocked by arginine methylester, an E3alpha-selective inhibitor. Treatment of myotubes with tumor necrosis factor alpha or interleukin 6 elicited marked increases in E3alpha-II but not E3alpha-I expression and ubiquitin conjugation activity in parallel. E3alpha-II transfection markedly accelerated ubiquitin conjugation to endogenous cellular proteins in muscle cultures. These findings show that E3alpha-II plays an important role in muscle protein catabolism during cancer cachexia and suggest that E3alpha-II is a potential therapeutic target for muscle wasting.