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Metabolic Consequences of Old-Age and Insulin Resistance in Skeletal Muscle
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Metabolic Consequences of Old-Age and Insulin Resistance in Skeletal Muscle

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (30 June 2020) | Viewed by 68203

Special Issue Editors

Prof. David M. Thomson

E-Mail Website
Guest Editor
Department of Physiology & Developmental Biology, Brigham Young University, Provo, UT 84602, USA
Interests: skeletal muscle; insulin resistance; sarcopenia; metabolism; exercise; hypertrophy; disuse atrophy; AMPK; mTOR; myogenesis; injury repair
Prof. Chad R. Hancock

E-Mail Website
Guest Editor
Department of Nutrition, Dietetics & Food Science, Brigham Young University, Provo, UT 84602, USA

Special Issue Information

Dear Colleagues,

Aging impacts skeletal muscle metabolic homeostasis in a variety of ways that can result in muscle dysfunction and lead to age-related muscle mass loss or sarcopenia. It is well established that insulin resistance, which is a feature of type 2 diabetes mellitus, leads to many of the same metabolic disturbances that occur in aged muscle. In this Special Issue entitled “Metabolic consequences of old-age and insulin resistance in skeletal muscle”, we will focus on the interdependent and independent effects of old age and insulin resistance on skeletal muscle metabolism (including lipid, carbohydrate and protein anabolism or catabolism). We aim to compile both original research and quality review articles with a broad range of perspectives on the topic, including work addressing the role of endocrine, inflammatory, redox and exercise related inputs on metabolism, as well as the signalling mechanisms that mediate those effects.

Prof. David M. Thomson
Prof. Chad R. Hancock
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Insulin
  • Skeletal muscle
  • Fatty acid oxidation
  • Sarcopenia
  • Protein synthesis
  • Glucose oxidation
  • Mitochondria
  • Oxidative stress
  • Exercise
  • Physical inactivity

Published Papers (7 papers)

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Review

15 pages, 3096 KiB  
Review
Excess Accumulation of Lipid Impairs Insulin Sensitivity in Skeletal Muscle
by Sung Sup Park and Young-Kyo Seo
Int. J. Mol. Sci. 2020, 21(6), 1949; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21061949 - 12 Mar 2020
Cited by 36 | Viewed by 6767
Abstract
Both glucose and free fatty acids (FFAs) are used as fuel sources for energy production in a living organism. Compelling evidence supports a role for excess fatty acids synthesized in intramuscular space or dietary intermediates in the regulation of skeletal muscle function. Excess [...] Read more.
Both glucose and free fatty acids (FFAs) are used as fuel sources for energy production in a living organism. Compelling evidence supports a role for excess fatty acids synthesized in intramuscular space or dietary intermediates in the regulation of skeletal muscle function. Excess FFA and lipid droplets leads to intramuscular accumulation of lipid intermediates. The resulting downregulation of the insulin signaling cascade prevents the translocation of glucose transporter to the plasma membrane and glucose uptake into skeletal muscle, leading to metabolic disorders such as type 2 diabetes. The mechanisms underlining metabolic dysfunction in skeletal muscle include accumulation of intracellular lipid derivatives from elevated plasma FFAs. This paper provides a review of the molecular mechanisms underlying insulin-related signaling pathways after excess accumulation of lipids. Full article
(This article belongs to the Special Issue Metabolic Consequences of Old-Age and Insulin Resistance in Skeletal Muscle)
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20 pages, 353 KiB  
Review
Influence of Exercise Training on Skeletal Muscle Insulin Resistance in Aging: Spotlight on Muscle Ceramides
by Paul T. Reidy, Ziad S. Mahmassani, Alec I. McKenzie, Jonathan J. Petrocelli, Scott A. Summers and Micah J. Drummond
Int. J. Mol. Sci. 2020, 21(4), 1514; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21041514 - 22 Feb 2020
Cited by 24 | Viewed by 3891
Abstract
Intramuscular lipid accumulation has been associated with insulin resistance (IR), aging, diabetes, dyslipidemia, and obesity. A substantial body of evidence has implicated ceramides, a sphingolipid intermediate, as potent antagonists of insulin action that drive insulin resistance. Indeed, genetic mouse studies that lower ceramides [...] Read more.
Intramuscular lipid accumulation has been associated with insulin resistance (IR), aging, diabetes, dyslipidemia, and obesity. A substantial body of evidence has implicated ceramides, a sphingolipid intermediate, as potent antagonists of insulin action that drive insulin resistance. Indeed, genetic mouse studies that lower ceramides are potently insulin sensitizing. Surprisingly less is known about how physical activity (skeletal muscle contraction) regulates ceramides, especially in light that muscle contraction regulates insulin sensitivity. The purpose of this review is to critically evaluate studies (rodent and human) concerning the relationship between skeletal muscle ceramides and IR in response to increased physical activity. Our review of the literature indicates that chronic exercise reduces ceramide levels in individuals with obesity, diabetes, or hyperlipidemia. However, metabolically healthy individuals engaged in increased physical activity can improve insulin sensitivity independent of changes in skeletal muscle ceramide content. Herein we discuss these studies and provide context regarding the technical limitations (e.g., difficulty assessing the myriad ceramide species, the challenge of obtaining information on subcellular compartmentalization, and the paucity of flux measurements) and a lack of mechanistic studies that prevent a more sophisticated assessment of the ceramide pathway during increased contractile activity that lead to divergences in skeletal muscle insulin sensitivity. Full article
(This article belongs to the Special Issue Metabolic Consequences of Old-Age and Insulin Resistance in Skeletal Muscle)
14 pages, 233 KiB  
Review
Targeting Age-Dependent Functional and Metabolic Decline of Human Skeletal Muscle: The Geroprotective Role of Exercise, Myokine IL-6, and Vitamin D
by Clara Crescioli
Int. J. Mol. Sci. 2020, 21(3), 1010; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21031010 - 04 Feb 2020
Cited by 25 | Viewed by 4919
Abstract
In the elderly, whole-body health largely relies on healthy skeletal muscle, which controls body stability, locomotion, and metabolic homeostasis. Age-related skeletal muscle structural/functional deterioration is associated with a higher risk of severe comorbid conditions and poorer outcomes, demanding major socioeconomic costs. Thus, the [...] Read more.
In the elderly, whole-body health largely relies on healthy skeletal muscle, which controls body stability, locomotion, and metabolic homeostasis. Age-related skeletal muscle structural/functional deterioration is associated with a higher risk of severe comorbid conditions and poorer outcomes, demanding major socioeconomic costs. Thus, the need for efficient so-called geroprotective strategies to improve resilience and ensure a good quality of life in older subjects is urgent. Skeletal muscle senescence and metabolic dysregulation share common cellular/intracellular mechanisms, potentially representing targets for intervention to preserve muscle integrity. Many factors converge in aging, and multifaceted approaches have been proposed as interventions, although they have often been inconclusive. Physical exercise can counteract aging and metabolic deficits, not only in maintaining tissue mass, but also by preserving tissue secretory function. Indeed, skeletal muscle is currently considered a proper secretory organ controlling distant organ functions through immunoactive regulatory small peptides called myokines. This review provides a current perspective on the main biomolecular mechanisms underlying age-dependent and metabolic deterioration of skeletal muscle, herein discussed as a secretory organ, the functional integrity of which largely depends on exercise and myokine release. In particular, muscle-derived interleukin (IL)-6 is discussed as a nutrient-level biosensor. Overall, exercise and vitamin D are addressed as optimal geroprotective strategies in view of their multi-target effects. Full article
(This article belongs to the Special Issue Metabolic Consequences of Old-Age and Insulin Resistance in Skeletal Muscle)
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Graphical abstract

21 pages, 1088 KiB  
Review
Inactivity and Skeletal Muscle Metabolism: A Vicious Cycle in Old Age
by Elena Rezuş, Alexandra Burlui, Anca Cardoneanu, Ciprian Rezuş, Cătălin Codreanu, Mirela Pârvu, Gabriela Rusu Zota and Bogdan Ionel Tamba
Int. J. Mol. Sci. 2020, 21(2), 592; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21020592 - 16 Jan 2020
Cited by 51 | Viewed by 24184
Abstract
Aging is an inevitable and gradually progressive process affecting all organs and systems. The musculoskeletal system makes no exception, elderly exhibit an increased risk of sarcopenia (low muscle mass),dynapenia (declining muscle strength), and subsequent disability. Whereas in recent years the subject of skeletal [...] Read more.
Aging is an inevitable and gradually progressive process affecting all organs and systems. The musculoskeletal system makes no exception, elderly exhibit an increased risk of sarcopenia (low muscle mass),dynapenia (declining muscle strength), and subsequent disability. Whereas in recent years the subject of skeletal muscle metabolic decline in the elderly has been gathering interest amongst researchers, as well as medical professionals, there are many challenges yet to be solved in order to counteract the effects of aging on muscle function efficiently. Noteworthy, it has been shown that aging individuals exhibit a decline in skeletal muscle metabolism, a phenomenon which may be linked to a number of predisposing (risk) factors such as telomere attrition, epigenetic changes, mitochondrial dysfunction, sedentary behavior (leading to body composition alterations), age-related low-grade systemic inflammation (inflammaging), hormonal imbalance, as well as a hypoproteic diet (unable to counterbalance the repercussions of the age-related increase in skeletal muscle catabolism). The present review aims to discuss the relationship between old age and muscle wasting in an effort to highlight the modifications in skeletal muscle metabolism associated with aging and physical activity. Full article
(This article belongs to the Special Issue Metabolic Consequences of Old-Age and Insulin Resistance in Skeletal Muscle)
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Graphical abstract

17 pages, 286 KiB  
Review
Sarcopenic Obesity, Insulin Resistance, and Their Implications in Cardiovascular and Metabolic Consequences
by So-hyeon Hong and Kyung Mook Choi
Int. J. Mol. Sci. 2020, 21(2), 494; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21020494 - 13 Jan 2020
Cited by 148 | Viewed by 10613
Abstract
The prevalence of sarcopenic obesity is increasing worldwide, particularly amongst aging populations. Insulin resistance is the core mechanism of sarcopenic obesity and is also associated with variable cardiometabolic diseases such as cardiovascular disease, type 2 diabetes mellitus, and non-alcoholic fatty liver disease. Fat [...] Read more.
The prevalence of sarcopenic obesity is increasing worldwide, particularly amongst aging populations. Insulin resistance is the core mechanism of sarcopenic obesity and is also associated with variable cardiometabolic diseases such as cardiovascular disease, type 2 diabetes mellitus, and non-alcoholic fatty liver disease. Fat accumulation in muscle tissue promotes a proinflammatory cascade and oxidative stress, leading to mitochondrial dysfunction, impaired insulin signaling, and muscle atrophy. To compound the problem, decreased muscle mass aggravates insulin resistance. In addition, the crosstalk between myokines and adipokines leads to negative feedback, which in turn aggravates sarcopenic obesity and insulin resistance. In this review, we focus on the molecular mechanisms linking sarcopenic obesity and insulin resistance with various biological pathways. We also discuss the impact and mechanism of sarcopenic obesity and insulin resistance on cardiometabolic disease. Full article
(This article belongs to the Special Issue Metabolic Consequences of Old-Age and Insulin Resistance in Skeletal Muscle)
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Graphical abstract

16 pages, 455 KiB  
Review
Increased Adenine Nucleotide Degradation in Skeletal Muscle Atrophy
by Spencer G. Miller, Paul S. Hafen and Jeffrey J. Brault
Int. J. Mol. Sci. 2020, 21(1), 88; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21010088 - 21 Dec 2019
Cited by 40 | Viewed by 7349
Abstract
Adenine nucleotides (AdNs: ATP, ADP, AMP) are essential biological compounds that facilitate many necessary cellular processes by providing chemical energy, mediating intracellular signaling, and regulating protein metabolism and solubilization. A dramatic reduction in total AdNs is observed in atrophic skeletal muscle across numerous [...] Read more.
Adenine nucleotides (AdNs: ATP, ADP, AMP) are essential biological compounds that facilitate many necessary cellular processes by providing chemical energy, mediating intracellular signaling, and regulating protein metabolism and solubilization. A dramatic reduction in total AdNs is observed in atrophic skeletal muscle across numerous disease states and conditions, such as cancer, diabetes, chronic kidney disease, heart failure, COPD, sepsis, muscular dystrophy, denervation, disuse, and sarcopenia. The reduced AdNs in atrophic skeletal muscle are accompanied by increased expression/activities of AdN degrading enzymes and the accumulation of degradation products (IMP, hypoxanthine, xanthine, uric acid), suggesting that the lower AdN content is largely the result of increased nucleotide degradation. Furthermore, this characteristic decrease of AdNs suggests that increased nucleotide degradation contributes to the general pathophysiology of skeletal muscle atrophy. In view of the numerous energetic, and non-energetic, roles of AdNs in skeletal muscle, investigations into the physiological consequences of AdN degradation may provide valuable insight into the mechanisms of muscle atrophy. Full article
(This article belongs to the Special Issue Metabolic Consequences of Old-Age and Insulin Resistance in Skeletal Muscle)
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31 pages, 3170 KiB  
Review
Quantification of Mitochondrial Oxidative Phosphorylation in Metabolic Disease: Application to Type 2 Diabetes
by Matthew T. Lewis, Jonathan D. Kasper, Jason N. Bazil, Jefferson C. Frisbee and Robert W. Wiseman
Int. J. Mol. Sci. 2019, 20(21), 5271; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20215271 - 24 Oct 2019
Cited by 22 | Viewed by 9966
Abstract
Type 2 diabetes (T2D) is a growing health concern with nearly 400 million affected worldwide as of 2014. T2D presents with hyperglycemia and insulin resistance resulting in increased risk for blindness, renal failure, nerve damage, and premature death. Skeletal muscle is a major [...] Read more.
Type 2 diabetes (T2D) is a growing health concern with nearly 400 million affected worldwide as of 2014. T2D presents with hyperglycemia and insulin resistance resulting in increased risk for blindness, renal failure, nerve damage, and premature death. Skeletal muscle is a major site for insulin resistance and is responsible for up to 80% of glucose uptake during euglycemic hyperglycemic clamps. Glucose uptake in skeletal muscle is driven by mitochondrial oxidative phosphorylation and for this reason mitochondrial dysfunction has been implicated in T2D. In this review we integrate mitochondrial function with physiologic function to present a broader understanding of mitochondrial functional status in T2D utilizing studies from both human and rodent models. Quantification of mitochondrial function is explained both in vitro and in vivo highlighting the use of proper controls and the complications imposed by obesity and sedentary lifestyle. This review suggests that skeletal muscle mitochondria are not necessarily dysfunctional but limited oxygen supply to working muscle creates this misperception. Finally, we propose changes in experimental design to address this question unequivocally. If mitochondrial function is not impaired it suggests that therapeutic interventions and drug development must move away from the organelle and toward the cardiovascular system. Full article
(This article belongs to the Special Issue Metabolic Consequences of Old-Age and Insulin Resistance in Skeletal Muscle)
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