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1.
Therapeutic approaches to preserve the musculature in Duchenne Muscular Dystrophy: The importance of the secondary therapies.
Angelini, G, Mura, G, Messina, G
Experimental cell research. 2022;(2):112968
Abstract
Muscular dystrophies (MDs) are heterogeneous diseases, characterized by primary wasting of skeletal muscle, which in severe cases, such as Duchenne Muscular Dystrophy (DMD), leads to wheelchair dependency, respiratory failure, and premature death. Research is ongoing to develop efficacious therapies, particularly for DMD. Most of the efforts, currently focusing on correcting or restoring the primary defect of MDs, are based on gene-addition, exon-skipping, stop codon read-through, and genome-editing. Although promising, most of them revealed several practical limitations. Shared knowledge in the field is that, in order to be really successful, any therapeutic approach has to rely on spared functional muscle tissue, restricting the number of patients eligible for clinical trials to the youngest and less compromised individuals. In line with this, many therapeutic strategies aim to preserve muscle tissue and function. This Review outlines the most interesting and recent studies addressing the secondary outcomes of DMD and how to better deliver the therapeutic agents. In the future, the effective treatment of DMD will likely require combinations of therapies addressing both the primary genetic defect and its consequences.
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2.
A new paradigm in sarcopenia: Cognitive impairment caused by imbalanced myokine secretion and vascular dysfunction.
Jo, D, Yoon, G, Kim, OY, Song, J
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2022;:112636
Abstract
Sarcopenia characterized by reduced skeletal muscle mass and decreased muscle strength is increasing in prevalence globally. The pathophysiology of sarcopenia is related to various factors including hormonal imbalance, increased intracellular oxidative stress, reduction of food intake, advanced age, low body mass index, and low physical activity. Recently, sarcopenia has been reported to be associated with cognitive decline, and the common risk factors between sarcopenia and memory loss were observed in cohort studies. Many researchers suggested that the prevalence of sarcopenia is associated with vascular disorder, such as atherosclerosis and alteration of intracellular mechanisms caused by changes in myokine secretion. We herein review the emerging evidence on the strong link between cognitive impairment and sarcopenia, focusing on myokine secretion and vascular dysfunction, and provide an understanding of the relevant mechanisms and crucial determinants in cognitive decline caused by sarcopenia.
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3.
Alteration of STIM1/Orai1-Mediated SOCE in Skeletal Muscle: Impact in Genetic Muscle Diseases and Beyond.
Conte, E, Imbrici, P, Mantuano, P, Coppola, MA, Camerino, GM, De Luca, A, Liantonio, A
Cells. 2021;(10)
Abstract
Intracellular Ca2+ ions represent a signaling mediator that plays a critical role in regulating different muscular cellular processes. Ca2+ homeostasis preservation is essential for maintaining skeletal muscle structure and function. Store-operated Ca2+ entry (SOCE), a Ca2+-entry process activated by depletion of intracellular stores contributing to the regulation of various function in many cell types, is pivotal to ensure a proper Ca2+ homeostasis in muscle fibers. It is coordinated by STIM1, the main Ca2+ sensor located in the sarcoplasmic reticulum, and ORAI1 protein, a Ca2+-permeable channel located on transverse tubules. It is commonly accepted that Ca2+ entry via SOCE has the crucial role in short- and long-term muscle function, regulating and adapting many cellular processes including muscle contractility, postnatal development, myofiber phenotype and plasticity. Lack or mutations of STIM1 and/or Orai1 and the consequent SOCE alteration have been associated with serious consequences for muscle function. Importantly, evidence suggests that SOCE alteration can trigger a change of intracellular Ca2+ signaling in skeletal muscle, participating in the pathogenesis of different progressive muscle diseases such as tubular aggregate myopathy, muscular dystrophy, cachexia, and sarcopenia. This review provides a brief overview of the molecular mechanisms underlying STIM1/Orai1-dependent SOCE in skeletal muscle, focusing on how SOCE alteration could contribute to skeletal muscle wasting disorders and on how SOCE components could represent pharmacological targets with high therapeutic potential.
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4.
Skeletal Muscle in ALS: An Unappreciated Therapeutic Opportunity?
Scaricamazza, S, Salvatori, I, Ferri, A, Valle, C
Cells. 2021;(3)
Abstract
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the selective degeneration of upper and lower motor neurons and by the progressive weakness and paralysis of voluntary muscles. Despite intense research efforts and numerous clinical trials, it is still an incurable disease. ALS had long been considered a pure motor neuron disease; however, recent studies have shown that motor neuron protection is not sufficient to prevent the course of the disease since the dismantlement of neuromuscular junctions occurs before motor neuron degeneration. Skeletal muscle alterations have been described in the early stages of the disease, and they seem to be mainly involved in the "dying back" phenomenon of motor neurons and metabolic dysfunctions. In recent years, skeletal muscles have been considered crucial not only for the etiology of ALS but also for its treatment. Here, we review clinical and preclinical studies that targeted skeletal muscles and discuss the different approaches, including pharmacological interventions, supplements or diets, genetic modifications, and training programs.
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5.
The many actions of insulin in skeletal muscle, the paramount tissue determining glycemia.
Sylow, L, Tokarz, VL, Richter, EA, Klip, A
Cell metabolism. 2021;(4):758-780
Abstract
As the principal tissue for insulin-stimulated glucose disposal, skeletal muscle is a primary driver of whole-body glycemic control. Skeletal muscle also uniquely responds to muscle contraction or exercise with increased sensitivity to subsequent insulin stimulation. Insulin's dominating control of glucose metabolism is orchestrated by complex and highly regulated signaling cascades that elicit diverse and unique effects on skeletal muscle. We discuss the discoveries that have led to our current understanding of how insulin promotes glucose uptake in muscle. We also touch upon insulin access to muscle, and insulin signaling toward glycogen, lipid, and protein metabolism. We draw from human and rodent studies in vivo, isolated muscle preparations, and muscle cell cultures to home in on the molecular, biophysical, and structural elements mediating these responses. Finally, we offer some perspective on molecular defects that potentially underlie the failure of muscle to take up glucose efficiently during obesity and type 2 diabetes.
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6.
Natural products and skeletal muscle health.
Qu, Z, Zhou, S, Li, P, Liu, C, Yuan, B, Zhang, S, Liu, A
The Journal of nutritional biochemistry. 2021;:108619
Abstract
Skeletal muscle (SkM) is essential for body movement, energy metabolism, and material metabolism, and directly influences the quality of human life. Aging, chronic diseases, and strenuous exercise often lead to various health problems associated with SkM, including muscle atrophy, loss of muscle mass and strength, and metabolic disorders. Various natural products (NaPs), mainly resveratrol (RES), quercetin (QUE), ursolic acid (UA), ecdysone (ECD; mainly 20-OH ECD, 20-HE), and vitamin D, have been reported to protect or regulate SkM health. Some of the products are functionally equivalent to sex hormones, and some are even referred to as "plant exercise pills." However, controversy persists regarding the role of NaPs in SkM health. Therefore, this review objectively summarizes the in vivo and vitro biological activities, molecular mechanisms, and clinical research results of studies on NaPs applied in the regulation of SkM health over the past decade. The present review could advance further research on NaPs and SkM health, and facilitate the revelation of new evidence that could facilitate the application of NaPs in ensuring SkM health.
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7.
Effects of Curcumin Supplementation on Inflammatory Markers, Muscle Damage, and Sports Performance during Acute Physical Exercise in Sedentary Individuals.
Dias, KA, da Conceição, AR, Oliveira, LA, Pereira, SMS, Paes, SDS, Monte, LF, Sarandy, MM, Novaes, RD, Gonçalves, RV, Della Lucia, CM
Oxidative medicine and cellular longevity. 2021;:9264639
Abstract
Exhaustive and acute unusual physical exercise leads to muscle damage. Curcumin has been widely studied due to the variety of its biological activities, attributed to its antioxidant and anti-inflammatory properties. Furthermore, it has shown positive effects on physical exercise practitioners. However, there is no literature consensus on the beneficial effects of curcumin in acute physical activities performed by sedentary individuals. Therefore, we systematically reviewed evidence from clinical trials on the main effects of curcumin supplementation on inflammatory markers, sports performance, and muscle damage during acute physical exercises in these individuals. We searched PubMed/MEDLINE, Scopus, Web of Science, and Embase databases, and only original studies were analyzed according to the PRISMA guidelines. The included studies were limited to supplementation of curcumin during acute exercise. A total of 5 studies were selected. Methodological quality assessments were examined using the SYRCLE's risk-of-bias tool. Most studies have shown positive effects of curcumin supplementation in sedentary individuals undergoing acute physical exercise. Overall, participants supplemented with curcumin showed less muscle damage, reduced inflammation, and better muscle performance. The studies showed heterogeneous data and exhibited methodological limitations; therefore, further research is necessary to ensure curcumin supplementation benefits during acute and high-intensity physical exercises. Additionally, mechanistic and highly controlled studies are required to improve the quality of the evidence and to elucidate other possible mechanisms. This study is registered with Prospero number CRD42021262718.
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8.
The role of AMPK in regulation of Na+,K+-ATPase in skeletal muscle: does the gauge always plug the sink?
Pirkmajer, S, Petrič, M, Chibalin, AV
Journal of muscle research and cell motility. 2021;(1):77-97
Abstract
AMP-activated protein kinase (AMPK) is a cellular energy gauge and a major regulator of cellular energy homeostasis. Once activated, AMPK stimulates nutrient uptake and the ATP-producing catabolic pathways, while it suppresses the ATP-consuming anabolic pathways, thus helping to maintain the cellular energy balance under energy-deprived conditions. As much as ~ 20-25% of the whole-body ATP consumption occurs due to a reaction catalysed by Na+,K+-ATPase (NKA). Being the single most important sink of energy, NKA might seem to be an essential target of the AMPK-mediated energy saving measures, yet NKA is vital for maintenance of transmembrane Na+ and K+ gradients, water homeostasis, cellular excitability, and the Na+-coupled transport of nutrients and ions. Consistent with the model that AMPK regulates ATP consumption by NKA, activation of AMPK in the lung alveolar cells stimulates endocytosis of NKA, thus suppressing the transepithelial ion transport and the absorption of the alveolar fluid. In skeletal muscles, contractions activate NKA, which opposes a rundown of transmembrane ion gradients, as well as AMPK, which plays an important role in adaptations to exercise. Inhibition of NKA in contracting skeletal muscle accentuates perturbations in ion concentrations and accelerates development of fatigue. However, different models suggest that AMPK does not inhibit or even stimulates NKA in skeletal muscle, which appears to contradict the idea that AMPK maintains the cellular energy balance by always suppressing ATP-consuming processes. In this short review, we examine the role of AMPK in regulation of NKA in skeletal muscle and discuss the apparent paradox of AMPK-stimulated ATP consumption.
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9.
The clinical relevance and mechanism of skeletal muscle wasting.
Duan, K, Gao, X, Zhu, D
Clinical nutrition (Edinburgh, Scotland). 2021;(1):27-37
Abstract
Skeletal muscle wasting occurs in both chronic and acute diseases. Increasing evidence has shown this debilitating process is associated with short- and long-term outcomes in critical, cancer and surgical patients. Both muscle quantity and quality, as reflected by the area and density of a given range of attenuation in CT scan, impact the patient prognosis. In addition, ultrasound and bioelectrical impedance analysis (BIA) are also widely used in the assessment of body composition due to their bedside viability and no radioactivity. Mechanism researches have revealed complicated pathways are involved in muscle wasting, which include altered IGF1-Akt-FoxO signaling, elevated levels of myostatin and activin A, activation of NF-κB pathway and glucocorticoid effects. Particularly, central nervous system (CNS) has been proven to participate in regulating muscle wasting in various conditions, such as infection and tumor. Several promising therapeutic agents have been under developing in the treatment of muscle atrophy, such as myostatin antagonist, ghrelin analog, non-steroidal selective androgen receptor modulators (SARMs). Notably, nutritional therapy is still the fundamental support in combating muscle wasting. However, the optimizing and tailored nutrition regimen relies on accurate metabolism measurement and large clinical trials in the future. Here, we will discuss the current understanding of muscle wasting and potential treatment in clinical practice.
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10.
The Validity of Ultrasound Technology in Providing an Indirect Estimate of Muscle Glycogen Concentrations Is Equivocal.
Bone, JL, Ross, ML, Tomcik, KA, Jeacocke, NA, McKay, AKA, Burke, LM
Nutrients. 2021;(7)
Abstract
Researchers and practitioners in sports nutrition would greatly benefit from a rapid, portable, and non-invasive technique to measure muscle glycogen, both in the laboratory and field. This explains the interest in MuscleSound®, the first commercial system to use high-frequency ultrasound technology and image analysis from patented cloud-based software to estimate muscle glycogen content from the echogenicity of the ultrasound image. This technique is based largely on muscle water content, which is presumed to act as a proxy for glycogen. Despite the promise of early validation studies, newer studies from independent groups reported discrepant results, with MuscleSound® scores failing to correlate with the glycogen content of biopsy-derived mixed muscle samples or to show the expected changes in muscle glycogen associated with various diet and exercise strategies. The explanation of issues related to the site of assessment do not account for these discrepancies, and there are substantial problems with the premise that the ratio of glycogen to water in the muscle is constant. Although further studies investigating this technique are warranted, current evidence that MuscleSound® technology can provide valid and actionable information around muscle glycogen stores is at best equivocal.