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Molecular Mechanism and Pathogenesis of Sarcopenia

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 October 2020) | Viewed by 67011

Special Issue Editors

1. Department of Medicine and Surgery, Lum Jean Monnet University, 70010 Casamassima, Italy
2. Department of Geriatrics, Neuroscience and Orthopedics, Fondazione Policlinico Universitario "A. Gemelli", IRCCS, 00168 Rome, Italy
Interests: autophagy; biogerontology; biomarkers; exosomes; inflamm-aging; metabolic markers; mitochondria; mitochondrial DNA; mitophagy; mitochondrial damage
Special Issues, Collections and Topics in MDPI journals
Fondazione Policlinico Universitario "A. Gemelli", IRCCS, 00168 Rome, Italy
Interests: geriatrics; nutrition; frailty; sarcopenia; cognitive function
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Sarcopenia, the progressive age-related loss of skeletal muscle mass and strength/function during aging, increases the risk of a vast array of adverse health outcomes, including falls, morbidity, loss of independence, disability, and mortality. Several processes and mechanisms have been indicated as contributors to age-related muscle tissue disruption. These include altered hormonal status, chronic inflammation, redox imbalance, loss of α-motor neurons, muscular mitochondrial dysfunction, altered myocyte autophagy, accelerated apoptosis of myonuclei, and impaired satellite cell function. This Special Issue is intended to bring together basic researchers and clinicians working in the area of sarcopenia in human and animal models to gain insights into molecular mechanisms involved in the pathophysiology of sarcopenia. The ultimate aims of this Special Issue are to shed light on biological targets for interventions against sarcopenia and to identify novel biomarkers for the condition.

We therefore invite you to submit your latest original research or review articles on sarcopenia to this Special Issue.

Dr. Anna Picca
Dr. Riccardo Calvani
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • muscle aging
  • functional impairment and frailty
  • mitochondrial dysfunction
  • cellular quality control
  • redox biology
  • inflammation
  • biomarkers
  • omics
  • gut microbiota
  • behavioral and pharmacological interventions

Published Papers (11 papers)

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Editorial

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4 pages, 212 KiB  
Editorial
Molecular Mechanism and Pathogenesis of Sarcopenia: An Overview
Int. J. Mol. Sci. 2021, 22(6), 3032; https://doi.org/10.3390/ijms22063032 - 16 Mar 2021
Cited by 17 | Viewed by 3472
Abstract
Sarcopenia involves a progressive age-related decline of skeletal muscle mass and strength/function [...] Full article
(This article belongs to the Special Issue Molecular Mechanism and Pathogenesis of Sarcopenia)

Research

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16 pages, 1533 KiB  
Article
The Gut-Muscle Axis in Older Subjects with Low Muscle Mass and Performance: A Proof of Concept Study Exploring Fecal Microbiota Composition and Function with Shotgun Metagenomics Sequencing
Int. J. Mol. Sci. 2020, 21(23), 8946; https://doi.org/10.3390/ijms21238946 - 25 Nov 2020
Cited by 53 | Viewed by 4095
Abstract
The gut microbiota could influence the pathophysiology of age-related sarcopenia through multiple mechanisms implying modulation of chronic inflammation and anabolic resistance. The aim of this study was to compare the fecal microbiota composition and functionality, assessed by shotgun metagenomics sequencing, between two groups [...] Read more.
The gut microbiota could influence the pathophysiology of age-related sarcopenia through multiple mechanisms implying modulation of chronic inflammation and anabolic resistance. The aim of this study was to compare the fecal microbiota composition and functionality, assessed by shotgun metagenomics sequencing, between two groups of elderly outpatients, differing only for the presence of primary sarcopenia. Five sarcopenic elderly subjects and twelve non-sarcopenic controls, classified according to lower limb function and bioimpedance-derived skeletal muscle index, provided a stool sample, which was analyzed with shotgun metagenomics approaches, to determine the overall microbiota composition, the representation of bacteria at the species level, and the prediction of bacterial genes involved in functional metabolic pathways. Sarcopenic subjects displayed different fecal microbiota compositions at the species level, with significant depletion of two species known for their metabolic capacity of producing short-chain fatty acids (SCFAs), Faecalibacterium prausnitzii and Roseburia inulinivorans, and of Alistipes shahii. Additionally, their fecal metagenome had different representation of genes belonging to 108 metabolic pathways, namely, depletion of genes involved in SCFA synthesis, carotenoid and isoflavone biotransformation, and amino acid interconversion. These results support the hypothesis of an association between microbiota and sarcopenia, indicating novel possible mediators, whose clinical relevance should be investigated in future studies. Full article
(This article belongs to the Special Issue Molecular Mechanism and Pathogenesis of Sarcopenia)
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Review

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20 pages, 959 KiB  
Review
Cancer-Associated Muscle Wasting—Candidate Mechanisms and Molecular Pathways
Int. J. Mol. Sci. 2020, 21(23), 9268; https://doi.org/10.3390/ijms21239268 - 04 Dec 2020
Cited by 19 | Viewed by 5083
Abstract
Excessive muscle loss is commonly observed in cancer patients and its association with poor prognosis has been well-established. Cancer-associated sarcopenia differs from age-related wasting in that it is not responsive to nutritional intervention and exercise. This is related to its unique pathogenesis, a [...] Read more.
Excessive muscle loss is commonly observed in cancer patients and its association with poor prognosis has been well-established. Cancer-associated sarcopenia differs from age-related wasting in that it is not responsive to nutritional intervention and exercise. This is related to its unique pathogenesis, a result of diverse and interconnected mechanisms including inflammation, disordered metabolism, proteolysis and autophagy. There is a growing body of evidence that suggests that the tumor is the driver of muscle wasting by its elaboration of mediators that influence each of these pro-sarcopenic pathways. In this review, evidence for these tumor-derived factors and putative mechanisms for inducing muscle wasting will be reviewed. Potential targets for future research and therapeutic interventions will also be reviewed. Full article
(This article belongs to the Special Issue Molecular Mechanism and Pathogenesis of Sarcopenia)
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18 pages, 2441 KiB  
Review
Exercise and the Cisd2 Prolongevity Gene: Two Promising Strategies to Delay the Aging of Skeletal Muscle
Int. J. Mol. Sci. 2020, 21(23), 9059; https://doi.org/10.3390/ijms21239059 - 28 Nov 2020
Cited by 10 | Viewed by 4026
Abstract
Aging is an evolutionally conserved process that limits life activity. Cellular aging is the result of accumulated genetic damage, epigenetic damage and molecular exhaustion, as well as altered inter-cellular communication; these lead to impaired organ function and increased vulnerability to death. Skeletal muscle [...] Read more.
Aging is an evolutionally conserved process that limits life activity. Cellular aging is the result of accumulated genetic damage, epigenetic damage and molecular exhaustion, as well as altered inter-cellular communication; these lead to impaired organ function and increased vulnerability to death. Skeletal muscle constitutes ~40% of the human body’s mass. In addition to maintaining skeletal structure and allowing locomotion, which enables essential daily activities to be completed, skeletal muscle also plays major roles in thermogenesis, metabolism and the functioning of the endocrine system. Unlike many other organs that have a defined size once adulthood is reached, skeletal muscle is able to alter its structural and functional properties in response to changes in environmental conditions. Muscle mass usually remains stable during early life; however, it begins to decline at a rate of ~1% year in men and ~0.5% in women after the age of 50 years. On the other hand, different exercise training regimens are able to restore muscle homeostasis at the molecular, cellular and organismal levels, thereby improving systemic health. Here we give an overview of the molecular factors that contribute to lifespan and healthspan, and discuss the effects of the longevity gene Cisd2 and middle-to-old age exercise on muscle metabolism and changes in the muscle transcriptome in mice during very old age. Full article
(This article belongs to the Special Issue Molecular Mechanism and Pathogenesis of Sarcopenia)
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16 pages, 529 KiB  
Review
Sarcopenia: Molecular Pathways and Potential Targets for Intervention
Int. J. Mol. Sci. 2020, 21(22), 8844; https://doi.org/10.3390/ijms21228844 - 22 Nov 2020
Cited by 48 | Viewed by 7408
Abstract
Aging is associated with sarcopenia. The loss of strength results in decreased muscle mass and motor function. This process accelerates the progressive muscle deterioration observed in older adults, favoring the presence of debilitating pathologies. In addition, sarcopenia leads to a decrease in quality [...] Read more.
Aging is associated with sarcopenia. The loss of strength results in decreased muscle mass and motor function. This process accelerates the progressive muscle deterioration observed in older adults, favoring the presence of debilitating pathologies. In addition, sarcopenia leads to a decrease in quality of life, significantly affecting self-sufficiency. Altogether, these results in an increase in economic resources from the National Health Systems devoted to mitigating this problem in the elderly, particularly in developed countries. Different etiological determinants are involved in the progression of the disease, including: neurological factors, endocrine alterations, as well as nutritional and lifestyle changes related to the adoption of more sedentary habits. Molecular and cellular mechanisms have not been clearly characterized, resulting in the absence of an effective treatment for sarcopenia. Nevertheless, physical activity seems to be the sole strategy to delay sarcopenia and its symptoms. The present review intends to bring together the data explaining how physical activity modulates at a molecular and cellular level all factors that predispose or favor the progression of this deteriorating pathology. Full article
(This article belongs to the Special Issue Molecular Mechanism and Pathogenesis of Sarcopenia)
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27 pages, 846 KiB  
Review
Impact of Mitophagy and Mitochondrial Unfolded Protein Response as New Adaptive Mechanisms Underlying Old Pathologies: Sarcopenia and Non-Alcoholic Fatty Liver Disease
Int. J. Mol. Sci. 2020, 21(20), 7704; https://doi.org/10.3390/ijms21207704 - 18 Oct 2020
Cited by 32 | Viewed by 5368
Abstract
Mitochondria are the first-line defense of the cell in the presence of stressing processes that can induce mitochondrial dysfunction. Under these conditions, the activation of two axes is accomplished, namely, (i) the mitochondrial unfolded protein response (UPRmt) to promote cell recovery [...] Read more.
Mitochondria are the first-line defense of the cell in the presence of stressing processes that can induce mitochondrial dysfunction. Under these conditions, the activation of two axes is accomplished, namely, (i) the mitochondrial unfolded protein response (UPRmt) to promote cell recovery and survival of the mitochondrial network; (ii) the mitophagy process to eliminate altered or dysfunctional mitochondria. For these purposes, the former response induces the expression of chaperones, proteases, antioxidant components and protein import and assembly factors, whereas the latter is signaled through the activation of the PINK1/Parkin and BNIP3/NIX pathways. These adaptive mechanisms may be compromised during aging, leading to the development of several pathologies including sarcopenia, defined as the loss of skeletal muscle mass and performance; and non-alcoholic fatty liver disease (NAFLD). These age-associated diseases are characterized by the progressive loss of organ function due to the accumulation of reactive oxygen species (ROS)-induced damage to biomolecules, since the ability to counteract the continuous and large generation of ROS becomes increasingly inefficient with aging, resulting in mitochondrial dysfunction as a central pathogenic mechanism. Nevertheless, the role of the integrated stress response (ISR) involving UPRmt and mitophagy in the development and progression of these illnesses is still a matter of debate, considering that some studies indicate that the prolonged exposure to low levels of stress may trigger these mechanisms to maintain mitohormesis, whereas others sustain that chronic activation of them could lead to cell death. In this review, we discuss the available research that contributes to unveil the role of the mitochondrial UPR in the development of sarcopenia, in an attempt to describe changes prior to the manifestation of severe symptoms; and in NAFLD, in order to prevent or reverse fat accumulation and its progression by means of suitable protocols to be addressed in future studies. Full article
(This article belongs to the Special Issue Molecular Mechanism and Pathogenesis of Sarcopenia)
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17 pages, 271 KiB  
Review
Muscle Wasting and Sarcopenia in Heart Failure—The Current State of Science
Int. J. Mol. Sci. 2020, 21(18), 6549; https://doi.org/10.3390/ijms21186549 - 08 Sep 2020
Cited by 57 | Viewed by 6162
Abstract
Sarcopenia is primarily characterized by skeletal muscle disturbances such as loss of muscle mass, quality, strength, and physical performance. It is commonly seen in elderly patients with chronic diseases. The prevalence of sarcopenia in chronic heart failure (HF) patients amounts to up to [...] Read more.
Sarcopenia is primarily characterized by skeletal muscle disturbances such as loss of muscle mass, quality, strength, and physical performance. It is commonly seen in elderly patients with chronic diseases. The prevalence of sarcopenia in chronic heart failure (HF) patients amounts to up to 20% and may progress into cardiac cachexia. Muscle wasting is a strong predictor of frailty and reduced survival in HF patients. Despite many different techniques and clinical tests, there is still no broadly available gold standard for the diagnosis of sarcopenia. Resistance exercise and nutritional supplementation represent the currently most used strategies against wasting disorders. Ongoing research is investigating skeletal muscle mitochondrial dysfunction as a new possible target for pharmacological compounds. Novel agents such as synthetic ghrelin and selective androgen receptor modulators (SARMs) seem promising in counteracting muscle abnormalities but their effectiveness in HF patients has not been assessed yet. In the last decades, many advances have been accomplished but sarcopenia remains an underdiagnosed pathology and more efforts are needed to find an efficacious therapeutic plan. The purpose of this review is to illustrate the current knowledge in terms of pathogenesis, diagnosis, and treatment of sarcopenia in order to provide a better understanding of wasting disorders occurring in chronic heart failure. Full article
(This article belongs to the Special Issue Molecular Mechanism and Pathogenesis of Sarcopenia)
21 pages, 846 KiB  
Review
Sarcopenia in Autoimmune and Rheumatic Diseases: A Comprehensive Review
Int. J. Mol. Sci. 2020, 21(16), 5678; https://doi.org/10.3390/ijms21165678 - 07 Aug 2020
Cited by 55 | Viewed by 6538
Abstract
Sarcopenia refers to a decrease in skeletal muscle mass and function. Because sarcopenia affects mortality, and causes significant disability, the clinical importance of sarcopenia is emerging. At first, sarcopenia was recognized as an age-related disease but, recently, it has been reported to be [...] Read more.
Sarcopenia refers to a decrease in skeletal muscle mass and function. Because sarcopenia affects mortality, and causes significant disability, the clinical importance of sarcopenia is emerging. At first, sarcopenia was recognized as an age-related disease but, recently, it has been reported to be prevalent also in younger patients with autoimmune diseases. Specifically, the association of sarcopenia and autoimmune diseases such as rheumatoid arthritis has been studied in detail. Although the pathogenesis of sarcopenia in autoimmune diseases has not been elucidated, chronic inflammation is believed to contribute to sarcopenia, and moreover the pathogenesis seems to be different depending on the respective underlying disease. The definition of sarcopenia differs among studies, which limits direct comparisons. Therefore, in this review, we cover various definitions of sarcopenia used in previous studies and highlight the prevalence of sarcopenia in diverse autoimmune diseases including rheumatoid arthritis, spondyloarthritis, systemic sclerosis, inflammatory bowel disease, and autoimmune diabetes. In addition, we cover the pathogenesis and treatment of sarcopenia in autoimmune and rheumatic diseases. This review provides a comprehensive understanding of sarcopenia in various autoimmune diseases and highlights the need for a consistent definition of sarcopenia. Full article
(This article belongs to the Special Issue Molecular Mechanism and Pathogenesis of Sarcopenia)
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16 pages, 773 KiB  
Review
Biomarkers of Physical Frailty and Sarcopenia: Coming up to the Place?
Int. J. Mol. Sci. 2020, 21(16), 5635; https://doi.org/10.3390/ijms21165635 - 06 Aug 2020
Cited by 39 | Viewed by 7379
Abstract
Physical frailty and sarcopenia (PF&S) recapitulates all the hallmarks of aging and has become a focus in geroscience. Factors spanning muscle-specific processes (e.g., mitochondrial dysfunction in skeletal myocytes) to systemic changes (e.g., inflammation and amino acid dysmetabolism) have been pinpointed as possible contributors [...] Read more.
Physical frailty and sarcopenia (PF&S) recapitulates all the hallmarks of aging and has become a focus in geroscience. Factors spanning muscle-specific processes (e.g., mitochondrial dysfunction in skeletal myocytes) to systemic changes (e.g., inflammation and amino acid dysmetabolism) have been pinpointed as possible contributors to PF&S pathophysiology. However, the search for PF&S biomarkers allowing the early identification and tracking of the condition over time is ongoing. This is mainly due to the phenotypic heterogeneity of PF&S, its unclear pathophysiology, and the frequent superimposition of other age-related conditions. Hence, presently, the identification of PF&S relies upon clinical, functional, and imaging parameters. The adoption of multi-marker approaches (combined with multivariate modeling) has shown great potential for addressing the complexity of PF&S pathophysiology and identifying candidate biological markers. Well-designed longitudinal studies are necessary for the incorporation of reliable biomarkers into clinical practice and for unveiling novel targets that are amenable to interventions. Full article
(This article belongs to the Special Issue Molecular Mechanism and Pathogenesis of Sarcopenia)
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12 pages, 662 KiB  
Review
Role of Age-Related Mitochondrial Dysfunction in Sarcopenia
Int. J. Mol. Sci. 2020, 21(15), 5236; https://doi.org/10.3390/ijms21155236 - 23 Jul 2020
Cited by 70 | Viewed by 10814
Abstract
Skeletal muscle aging is associated with a significant loss of skeletal muscle strength and power (i.e., dynapenia), muscle mass and quality of life, a phenomenon known as sarcopenia. This condition affects nearly one-third of the older population and is one of the main [...] Read more.
Skeletal muscle aging is associated with a significant loss of skeletal muscle strength and power (i.e., dynapenia), muscle mass and quality of life, a phenomenon known as sarcopenia. This condition affects nearly one-third of the older population and is one of the main factors leading to negative health outcomes in geriatric patients. Notwithstanding the exact mechanisms responsible for sarcopenia are not fully understood, mitochondria have emerged as one of the central regulators of sarcopenia. In fact, there is a wide consensus on the assumption that the loss of mitochondrial integrity in myocytes is the main factor leading to muscle degeneration. Mitochondria are also key players in senescence. It has been largely proven that the modulation of mitochondrial functions can induce the death of senescent cells and that removal of senescent cells improves musculoskeletal health, quality, and function. In this review, the crosstalk among mitochondria, cellular senescence, and sarcopenia will be discussed with the aim to elucidate the role that the musculoskeletal cellular senescence may play in the onset of sarcopenia through the mediation of mitochondria. Full article
(This article belongs to the Special Issue Molecular Mechanism and Pathogenesis of Sarcopenia)
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20 pages, 2826 KiB  
Review
Novel Insights into the Pathogenesis of Spinal Sarcopenia and Related Therapeutic Approaches: A Narrative Review
Int. J. Mol. Sci. 2020, 21(8), 3010; https://doi.org/10.3390/ijms21083010 - 24 Apr 2020
Cited by 9 | Viewed by 5458
Abstract
Spinal sarcopenia is a complex and multifactorial disorder associated with a loss of strength, increased frailty, and increased risks of fractures and falls. In addition, spinal sarcopenia has been associated with lumbar spine disorders and osteoporosis, which renders making decisions on treatment modalities [...] Read more.
Spinal sarcopenia is a complex and multifactorial disorder associated with a loss of strength, increased frailty, and increased risks of fractures and falls. In addition, spinal sarcopenia has been associated with lumbar spine disorders and osteoporosis, which renders making decisions on treatment modalities difficult. Patients with spinal sarcopenia typically exhibit lower cumulative survival, a higher risk of in-hospital complications, prolonged hospital stays, higher postoperative costs, and higher rates of blood transfusion after thoracolumbar spine surgery. Several studies have focused on the relationships between spinal sarcopenia, appendicular muscle mass, and bone-related problems—such as osteoporotic fractures and low bone mineral density—and malnutrition and vitamin D deficiency. Although several techniques are available for measuring sarcopenia, each of them has its advantages and shortcomings. For treating spinal sarcopenia, nutrition, physical therapy, and medication have been proven to be effective; regenerative therapeutic options seem to be promising owing to their repair and regeneration potential. Therefore, in this narrative review, we summarize the characteristics, detection methodologies, and treatment options for spinal sarcopenia, as well as its role in spinal disorders. Full article
(This article belongs to the Special Issue Molecular Mechanism and Pathogenesis of Sarcopenia)
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