Skeletal muscle atrophy is a pathological condition mainly characterized by a loss of muscular mass and the contractile capacity of the skeletal muscle as a consequence of muscular weakness and decreased force generation. Cachexia is defined as a pathological condition secondary to illness characterized by the progressive loss of muscle mass with or without loss of fat mass and with concomitant diminution of muscle strength. The molecular mechanisms involved in cachexia include oxidative stress, protein synthesis/degradation imbalance, autophagy deregulation, increased myonuclear apoptosis, and mitochondrial dysfunction. Oxidative stress is one of the most common mechanisms of cachexia caused by different factors. It results in increased ROS levels, increased oxidation-dependent protein modification, and decreased antioxidant system functions. In this review, we will describe the importance of oxidative stress in skeletal muscles, its sources, and how it can regulate protein synthesis/degradation imbalance, autophagy deregulation, increased myonuclear apoptosis, and mitochondrial dysfunction involved in cachexia.

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Role of Oxidative Stress as Key Regulator of Muscle Wasting during Cachexia.

Heart failure represents a systemic disease with profound effects on multiple peripheral tissues including skeletal muscle. Within the context of heart failure, perturbations in skeletal muscle physiology, structure, and function strongly contribute to exercise intolerance and the morbidity of this devastating disease. There is growing evidence that chronic heart failure imparts specific pathological changes within skeletal muscle beds resulting in muscle dysfunction and tissue atrophy. Mechanistically, systemic and local inflammatory responses drive critical aspects of this pathology. In this review, we will discuss pathological mechanisms that drive skeletal muscle inflammation and highlight emerging roles for distinct innate immune subsets that reside within damage muscle tissue focusing on the recently described embryonic and monocyte-derived macrophage lineages. Within this context, we will discuss how immune mechanisms can be differentially targeted to stimulate skeletal muscle inflammation, catabolism, fiber atrophy, and regeneration.

Skeletal muscle inflammation and atrophy in heart failure

This year, two new consensus conferences on the diagnosis and management of sarcopenia have been published. Both confirm the need to screen for sarcopenia in older persons. Suggested screening approaches are the SARC-F, the Ishii screening test, or grip strength. It should be recognized that grip strength was suggested for screening by one consensus group and as part of the diagnosis by the other. Measuring mid-calf muscle circumference improves the sensitivity and specificity of the SARC-F when it is compared with the consensus definitions. A number of consensus definitions for sarcopenia have been developed. All require either functional impairment (slow walking speed) or grip strength together with a low muscle mass. While the persons diagnosed by any of these definitions overlap, they all have different sensitivity and specificity when compared with one another or functional outcomes due to the different cut-off points. The Asian Group made it clear that cut-offs are very different for persons with Asian ethnicity compared with Europeans. [These definitions have led to the International Classification of Disease (10th edition) to recognize sarcopenia as an independent condition (M62.84)]. There are a number of different methods available to measure lean body mass including air displacement plethysmography, bioelectrical impedance analyses, dual-energy X-ray absorptiometry, and ultrasound. Each of these methods has been demonstrated to have problems in accurately determining muscle mass. Recently, D3-creatine dilution has been demonstrated to be more accurate in measuring muscle mass and more strongly related to physical performance. While age-related sarcopenia is considered to be primary sarcopenia, a number of disease states, for example, diabetes mellitus, male hypogonadism, and chronic obstructive pulmonary disease can produce secondary sarcopenia. Cachexia is a complex metabolism disorder leading to anorexia, muscle wasting, and loss of fat. The Glasgow Prognostic Score (low serum albumin and elevated C-reactive protein) can be used to distinguish secondary sarcopenia from cachexia. The advent of patient-centred (P4) care has increased attention to the fact that different molecular changes can result in the need to have different therapeutic approaches to similar conditions such as sarcopenia (Table 1). In this issue of the journal, Riuzzi et al. highlight that sarcopenia can result from a variety of molecular changes resulting in changes in myofibre metabolism and alterations in satellite cell properties. Abnormalities in these pathways can be due to insulin growth factor-1/insulin receptors, activin (myostatin) receptors, tropomysin receptor, kinase C receptors (neurotrophin and G-protein receptors), a variety of cytokines, and testosterone through activation of β-catenin. Thus, in the long run, the ideal treatment of sarcopenia will involve identification of the aberrant molecular pathway and the possible hormone causing this imbalance. At present, the treatment of sarcopenia is focused on resistance exercise. The use of leucine essential amino acids and/or β-hydroxybutyrate has not been clearly established but would seem a reasonable adjunct in persons with low protein intake. Drugs that have potential to treat sarcopenia include testosterone and anabolic steroids, myostatin antibodies, activin receptor antibodies, and the ghrelin agonist, anamorelin. There is also interest in the role of beta-blockade, some angiotensin-converting enzyme inhibitors, and sarconeos, which activates the MAS (angiotensin-1) receptor. A recent study suggested that metformin may improve mobility in persons with diabetes mellitus. Still highly experimental but likely to play a role in the future management of sarcopenia are CRISPR techniques and possibly stem cell therapy. EDITOR IAL

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jcsm.12386

Treatment of sarcopenia: the road to the future.

Skeletal muscle atrophy is characterized by the degradation of myofibrillar proteins, such as myosin heavy chain or troponin. An increase in the expression of two muscle-specific E3 ligases, atrogin-1 and MuRF-1, and oxidative stress are involved in muscle atrophy. Patients with chronic liver diseases (CLD) develop muscle wasting. Several bile acids increase in plasma during cholestatic CLD, among them, cholic acid (CA) and deoxycholic acid (DCA). The receptor for bile acids, TGR5, is expressed in healthy skeletal muscles. TGR5 is involved in the regulation of muscle differentiation and metabolic changes. In this paper, we evaluated the participation of DCA and CA in the generation of an atrophic condition in myotubes and isolated fibers from the muscle extracted from wild-type (WT) and TGR5-deficient (TGR5-/- ) male mice. The results show that DCA and CA induce a decrease in diameter, and myosin heavy chain (MHC) protein levels, two typical atrophic features in C2 C12 myotubes. We also observed similar results when INT-777 agonists activated the TGR5 receptor. To evaluate the participation of TGR5 in muscle atrophy induced by DCA and CA, we used a culture of muscle fiber isolated from WT and TGR5-/- mice. Our results show that DCA and CA decrease the fiber diameter and MHC protein levels, and there is an increase in atrogin-1, MuRF-1, and oxidative stress in WT fibers. The absence of TGR5 in fibers abolished all these effects induced by DCA and CA. Thus, we demonstrated that CS and deoxycholic acid induce skeletal muscle atrophy through TGR5 receptor.

Cholic acid and deoxycholic acid induce skeletal muscle atrophy through a mechanism dependent on TGR5 receptor.

Angiotensin converting enzyme-2 (ACE2) is a multifunctional transmembrane protein recently recognised as the entry receptor of the virus causing COVID-19. In the renin-angiotensin system (RAS), ACE2 cleaves angiotensin II (Ang II) into angiotensin 1-7 (Ang 1-7), which is considered to exert cellular responses to counteract the activation of the RAS primarily through a receptor, Mas, in multiple organs including skeletal muscle. Previous studies have provided abundant evidence suggesting that Ang 1-7 modulates multiple signalling pathways leading to protection from pathological muscle remodelling and muscle insulin resistance. In contrast, there is relatively little evidence to support the protective role of ACE2 in skeletal muscle. The potential contribution of endogenous ACE2 to the regulation of Ang 1-7-mediated protection of these muscle pathologies is discussed in this review. Recent studies have suggested that ACE2 protects against ageing-associated muscle wasting (sarcopenia) through its function to modulate molecules outside of the RAS. Thus, the potential association of sarcopenia with ACE2 and the associated molecules outside of RAS is also presented herein. Further, we introduce the transcriptional regulation of muscle ACE2 by drugs or exercise, and briefly discuss the potential role of ACE2 in the development of COVID-19.

ACE2, angiotensin 1-7 and skeletal muscle: review in the era of COVID-19.

Purpose of reviewSkeletal muscle can be affected by many physiological and pathological conditions that contribute to the development of muscle weakness, including skeletal muscle loss, inflammatory processes, or fibrosis. Therefore, research into therapeutic treatment alternatives or alleviation of

Dominga Garcia

Papers

Skeletal muscle wasting: New role of nonclassical renin-angiotensin system