Beneficial Effects and Limitations of Strategies (Nutritional or Other) to Limit Muscle Wasting due to Normal Aging

Muscle wasting is a frequently observed, inflammation-driven condition in aging and disease, known as sarcopenia and cachexia. Current treatment strategies target the muscle directly and are often not able to reverse the process. Because a reduced gut function is related to systemic inflammation, this might be an indirect target to ameliorate muscle wasting, by administering pro-, pre-, and synbiotics. Therefore, this review aimed to study the potential of pro-, pre-, and synbiotics to treat muscle wasting and to elucidate which metabolites and mechanisms affect the organ crosstalk in cachexia. Overall, the literature shows that Lactobacillus species pluralis (spp.) and possibly other genera, such as Bifidobacterium, can ameliorate muscle wasting in mouse models. The beneficial effects of Lactobacillus spp. supplementation may be attributed to its potential to improve microbiome balance and to its reported capacity to reduce gut permeability. A subsequent literature search revealed that the reduction of a high gut permeability coincided with improved muscle mass or strength, which shows an association between gut permeability and muscle mass. A possible working mechanism is proposed, involving lactate, butyrate, and reduced inflammation in gut–brain–muscle crosstalk. Thus, reducing gut permeability via Lactobacillus spp. supplementation could be a potential treatment strategy for muscle wasting.

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Is Exercise Training Appropriate for Patients With Advanced Heart Failure Receiving Continuous Inotropic Infusion? A Review

Clinical Medicine Insights Cardiology ◽

10.1177/1179546817751438 ◽

2018 ◽

Vol 12 ◽

pp. 117954681775143 ◽

Cited By ~ 2

Author(s):

Eisuke Amiya ◽

Masanobu Taya

Keyword(s):

Heart Failure ◽

Exercise Training ◽

Vascular Function ◽

Muscle Wasting ◽

Severe Heart Failure ◽

Advanced Heart Failure ◽

Autonomic Balance ◽

Beneficial Effects ◽

Rehabilitation Programs ◽

Patients With Heart Failure

Exercise-based rehabilitation programs have been reported to have beneficial effects for patients with heart failure. However, there is little evidence about whether this is the case in patients with more severe heart failure. In particular, there is a question in the clinical setting whether patients with advanced heart failure and continuous inotropic infusion should be prescribed exercise training. In contrast, many studies conclude that prolonged immobility associated with heart failure profoundly impairs physical function and promotes muscle wasting that could further hasten the course of heart failure. By contrast, exercise training has various effects not only in improving exercise capacity but also on vascular function, skeletal muscle, and autonomic balance. In this review, we summarize the effectiveness and discuss methods of exercise training in patients with advanced heart failure receiving continuous inotropic agents such as dobutamine.

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Targeting the Activin Receptor Signaling to Counteract the Multi-Systemic Complications of Cancer and Its Treatments

Cells ◽

10.3390/cells10030516 ◽

2021 ◽

Vol 10 (3) ◽

pp. 516

Author(s):

Juha J. Hulmi ◽

Tuuli A. Nissinen ◽

Fabio Penna ◽

Andrea Bonetto

Keyword(s):

Poor Prognosis ◽

Muscle Wasting ◽

Preclinical Models ◽

Systemic Complications ◽

Activin Receptor ◽

Downstream Signaling ◽

Beneficial Effects ◽

Tumor Bearing

Muscle wasting, i.e., cachexia, frequently occurs in cancer and associates with poor prognosis and increased morbidity and mortality. Anticancer treatments have also been shown to contribute to sustainment or exacerbation of cachexia, thus affecting quality of life and overall survival in cancer patients. Pre-clinical studies have shown that blocking activin receptor type 2 (ACVR2) or its ligands and their downstream signaling can preserve muscle mass in rodents bearing experimental cancers, as well as in chemotherapy-treated animals. In tumor-bearing mice, the prevention of skeletal and respiratory muscle wasting was also associated with improved survival. However, the definitive proof that improved survival directly results from muscle preservation following blockade of ACVR2 signaling is still lacking, especially considering that concurrent beneficial effects in organs other than skeletal muscle have also been described in the presence of cancer or following chemotherapy treatments paired with counteraction of ACVR2 signaling. Hence, here, we aim to provide an up-to-date literature review on the multifaceted anti-cachectic effects of ACVR2 blockade in preclinical models of cancer, as well as in combination with anticancer treatments.

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

Physiological Reviews ◽

10.1152/physrev.00028.2007 ◽

2008 ◽

Vol 88 (2) ◽

pp. 729-767 ◽

Cited By ~ 234

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.

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Low-level laser prevents doxorubicin-induced skeletal muscle atrophy by modulating AMPK/SIRT1/PCG-1α-mediated mitochondrial function, apoptosis and up-regulation of pro-inflammatory responses

Cell & Bioscience ◽

10.1186/s13578-021-00719-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Hsiu-Chung Ou ◽

Pei-Ming Chu ◽

Yu-Ting Huang ◽

Hui-Ching Cheng ◽

Wan-Ching Chou ◽

...

Keyword(s):

Oxidative Stress ◽

Muscle Atrophy ◽

Muscle Wasting ◽

Inflammatory Responses ◽

C2c12 Cells ◽

Skeletal Muscle Atrophy ◽

C2c12 Myoblast ◽

Protective Effects ◽

Low Level ◽

Beneficial Effects

Abstract Background Doxorubicin (Dox) is a widely used anthracycline drug to treat cancer, yet numerous adverse effects influencing different organs may offset the treatment outcome, which in turn affects the patient’s quality of life. Low-level lasers (LLLs) have resulted in several novel indications in addition to traditional orthopedic conditions, such as increased fatigue resistance and muscle strength. However, the mechanisms by which LLL irradiation exerts beneficial effects on muscle atrophy are still largely unknown. Results The present study aimed to test our hypothesis that LLL irradiation protects skeletal muscles against Dox-induced muscle wasting by using both animal and C2C12 myoblast cell models. We established SD rats treated with 4 consecutive Dox injections (12 mg/kg cumulative dose) and C2C12 myoblast cells incubated with 2 μM Dox to explore the protective effects of LLL irradiation. We found that LLL irradiation markedly alleviated Dox-induced muscle wasting in rats. Additionally, LLL irradiation inhibited Dox-induced mitochondrial dysfunction, apoptosis, and oxidative stress via the activation of AMPK and upregulation of SIRT1 with its downstream signaling PGC-1α. These aforementioned beneficial effects of LLL irradiation were reversed by knockdown AMPK, SIRT1, and PGC-1α in C2C12 cells transfected with siRNA and were negated by cotreatment with mitochondrial antioxidant and P38MAPK inhibitor. Therefore, AMPK/SIRT1/PGC-1α pathway activation may represent a new mechanism by which LLL irradiation exerts protection against Dox myotoxicity through preservation of mitochondrial homeostasis and alleviation of oxidative stress and apoptosis. Conclusion Our findings may provide a novel adjuvant intervention that can potentially benefit cancer patients from Dox-induced muscle wasting.

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Curcumin and Resveratrol Improve Muscle Function and Structure through Attenuation of Proteolytic Markers in Experimental Cancer-Induced Cachexia

Molecules ◽

10.3390/molecules26164904 ◽

2021 ◽

Vol 26 (16) ◽

pp. 4904

Author(s):

Antonio Penedo-Vázquez ◽

Xavier Duran ◽

Javier Mateu ◽

Adrián López-Postigo ◽

Esther Barreiro

Keyword(s):

Signaling Pathways ◽

Muscle Wasting ◽

Troponin I ◽

Total Body Weight ◽

Sirtuin 1 ◽

Limb Muscle ◽

Cross Sectional ◽

Therapeutic Implications ◽

Beneficial Effects ◽

Muscle Mass Loss

Muscle wasting and cachexia are prominent comorbidities in cancer. Treatment with polyphenolic compounds may partly revert muscle wasting. We hypothesized that treatment with curcumin or resveratrol in cancer cachectic mice may improve muscle phenotype and total body weight through attenuation of several proteolytic and signaling mechanisms in limb muscles. In gastrocnemius and soleus muscles of cancer cachectic mice (LP07 adenocarcinoma cells, N = 10/group): (1) LC-induced cachexia, (2) LC-cachexia+curcumin, and (3) LC-cachexia + resveratrol, muscle structure and damage (including blood troponin I), sirtuin-1, proteolytic markers, and signaling pathways (NF-κB and FoxO3) were explored (immunohistochemistry and immunoblotting). Compared to nontreated cachectic mice, in LC-cachexia + curcumin and LC-cachexia + resveratrol groups, body and muscle weights (gastrocnemius), limb muscle strength, muscle damage, and myofiber cross-sectional area improved, and in both muscles, sirtuin-1 increased, while proteolysis (troponin I), proteolytic markers, and signaling pathways were attenuated. Curcumin and resveratrol elicited beneficial effects on fast- and slow-twitch limb muscle phenotypes in cachectic mice through sirtuin-1 activation, attenuation of atrophy signaling pathways, and proteolysis in cancer cachectic mice. These findings have future therapeutic implications as these natural compounds, separately or in combination, may be used in clinical settings of muscle mass loss and dysfunction including cancer cachexia.

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FRZB and melusin, overexpressed in LGMD2A, regulate integrin β1D isoform replacement altering myoblast fusion and the integrin-signalling pathway

Expert Reviews in Molecular Medicine ◽

10.1017/erm.2017.3 ◽

2017 ◽

Vol 19 ◽

Cited By ~ 5

Author(s):

Oihane Jaka ◽

Leire Casas-Fraile ◽

Margarita Azpitarte ◽

Ana Aiastui ◽

Adolfo López de Munain ◽

...

Keyword(s):

Muscle Wasting ◽

Primary Cultures ◽

Myoblast Fusion ◽

Signalling Pathway ◽

Negative Regulator ◽

Muscle Degeneration ◽

Beneficial Effects ◽

Progressive Degeneration ◽

Positive Regulators

Limb-girdle muscular dystrophy type 2A (LGMD2A) is characterised by muscle wasting and progressive degeneration of proximal muscles because of mutations in the CAPN3 gene. However, the underlying pathophysiological mechanisms of muscle degeneration are still not well understood. The objective of this study was to assess the relevance of genes with differential expression in the muscle of LGMD2A patients. For this purpose, we analysed their in vitro expression in primary cultures of human myoblasts and myotubes. Abnormal fusion was observed in the myotubes of these patients, which may be explained by the lack of physiological replacement of integrin β1D. Owing to this observation, we focused on deregulated genes coding proteins that directly interact with integrin, ITGB1BP2 and CD9, as well as FRZB gene, because of its in vitro upregulation in myotubes. Silencing studies established that these genes are closely regulated, CD9 and FRZB being positive regulators of the expression of ITGB1BP2, and in turn, this gene being a negative regulator of the expression of FRZB. Interestingly, we observed that FRZB regulates integrin β1D expression, its silencing increasing integrin β1D expression to levels similar to those in controls. Finally, the administration of LiCl, an enhancer of the Wnt-signalling pathway showed similar experimentally beneficial effects, suggesting FRZB silencing or LiCl administration as potential therapeutic targets, though further studies are required.

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Nuclear receptors in disease: the oestrogen receptors

Essays in Biochemistry ◽

10.1042/bse0400157 ◽

2004 ◽

Vol 40 ◽

pp. 157-167 ◽

Cited By ~ 18

Author(s):

Maria Nilsson ◽

Karin Dahlman-Wright ◽

Jan-Åke Gustafsson

Keyword(s):

Nuclear Receptors ◽

Target Genes ◽

Receptor Subtype ◽

Target Tissue ◽

Oestrogen Receptors ◽

Nucleotide Polymorphisms ◽

Cell Type ◽

Single Nucleotide ◽

Beneficial Effects ◽

The Family

For several decades, it has been known that oestrogens are essential for human health. The discovery that there are two oestrogen receptors (ERs), ERalpha and ERbeta, has facilitated our understanding of how the hormone exerts its physiological effects. The ERs belong to the family of ligand-activated nuclear receptors, which act by modulating the expression of target genes. Studies of ER-knockout (ERKO) mice have been instrumental in defining the relevance of a given receptor subtype in a certain tissue. Phenotypes displayed by ERKO mice suggest diseases in which dysfunctional ERs might be involved in aetiology and pathology. Association between single-nucleotide polymorphisms (SNPs) in ER genes and disease have been demonstrated in several cases. Selective ER modulators (SERMs), which are selective with regard to their effects in a certain cell type, already exist. Since oestrogen has effects in many tissues, the goal with a SERM is to provide beneficial effects in one target tissue while avoiding side effects in others. Refined SERMs will, in the future, provide improved therapeutic strategies for existing and novel indications.

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The ubiquitin–proteasome system and skeletal muscle wasting

Essays in Biochemistry ◽

10.1042/bse0410173 ◽

2005 ◽

Vol 41 ◽

pp. 173-186 ◽

Cited By ~ 110

Author(s):

Didier Attaix ◽

Sophie Ventadour ◽

Audrey Codran ◽

Daniel Béchet ◽

Daniel Taillandier ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Wasting ◽

Proteolytic Enzymes ◽

Cathepsin L ◽

Ubiquitin Proteasome System ◽

Complete Breakdown ◽

Skeletal Muscle Proteins ◽

Ubiquitin Proteasome ◽

Tripeptidyl Peptidase Ii ◽

F Box Protein

The ubiquitin–proteasome system (UPS) is believed to degrade the major contractile skeletal muscle proteins and plays a major role in muscle wasting. Different and multiple events in the ubiquitination, deubiquitination and proteolytic machineries are responsible for the activation of the system and subsequent muscle wasting. However, other proteolytic enzymes act upstream (possibly m-calpain, cathepsin L, and/or caspase 3) and downstream (tripeptidyl-peptidase II and aminopeptidases) of the UPS, for the complete breakdown of the myofibrillar proteins into free amino acids. Recent studies have identified a few critical proteins that seem necessary for muscle wasting {i.e. the MAFbx (muscle atrophy F-box protein, also called atrogin-1) and MuRF-1 [muscle-specific RING (really interesting new gene) finger 1] ubiquitin–protein ligases}. The characterization of their signalling pathways is leading to new pharmacological approaches that can be useful to block or partially prevent muscle wasting in human patients.

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