Emerging Mechanisms of Skeletal Muscle Homeostasis and Cachexia: The SUMO Perspective.

Mobility is an intrinsic feature of the animal kingdom that stimulates evolutionary processes and determines the biological success of animals. Skeletal muscle is the primary driver of voluntary movements. Besides, skeletal muscles have an immense impact on regulating glucose, amino acid, and lipid homeostasis. Muscle atrophy/wasting conditions are accompanied by a drastic effect on muscle function and disrupt steady-state muscle physiology. Cachexia is a complex multifactorial muscle wasting syndrome characterized by extreme loss of skeletal muscle mass, resulting in a dramatic decrease in life quality and reported mortality in more than 30% of patients with advanced cancers. The lack of directed treatments to prevent or relieve muscle loss indicates our inadequate knowledge of molecular mechanisms involved in muscle cell organization and the molecular etiology of cancer-induced cachexia (CIC). This review highlights the latest knowledge of regulatory mechanisms involved in maintaining muscle function and their deregulation in wasting syndromes, particularly in cachexia. Recently, protein posttranslational modification by the small ubiquitin-like modifier (SUMO) has emerged as a key regulatory mechanism of protein function with implications for different aspects of cell physiology and diseases. We also review an atypical association of SUMO-mediated pathways in this context and deliberate on potential treatment strategies to alleviate muscle atrophy.

Interdisciplinary management of FGF23-related phosphate wasting syndromes: a Consensus Statement on the evaluation, diagnosis and care of patients with X-linked hypophosphataemia.

X-linked hypophosphataemia (XLH) is the most frequent cause of hypophosphataemia-associated rickets of genetic origin and is associated with high levels of the phosphaturic hormone fibroblast growth factor 23 (FGF23). In addition to rickets and osteomalacia, patients with XLH have a heavy disease burden with enthesopathies, osteoarthritis, pseudofractures and dental complications, all of which contribute to reduced quality of life. This Consensus Statement presents the outcomes of a working group of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases, and provides robust clinical evidence on management in XLH, with an emphasis on patients' experiences and needs. During growth, conventional treatment with phosphate supplements and active vitamin D metabolites (such as calcitriol) improves growth, ameliorates leg deformities and dental manifestations, and reduces pain. The continuation of conventional treatment in symptom-free adults is still debated. A novel therapeutic approach is the monoclonal anti-FGF23 antibody burosumab. Although promising, further studies are required to clarify its long-term efficacy, particularly in adults. Given the diversity of symptoms and complications, an interdisciplinary approach to management is of paramount importance. The focus of treatment should be not only on the physical manifestations and challenges associated with XLH and other FGF23-mediated hypophosphataemia syndromes, but also on the major psychological and social impact of the disease.

Pro-cachectic factors link experimental and human chronic kidney disease to skeletal muscle wasting programs.

Skeletal muscle wasting is commonly associated with chronic kidney disease (CKD), resulting in increased morbidity and mortality. However, the link between kidney and muscle function remains poorly understood. Here, we took a complementary interorgan approach to investigate skeletal muscle wasting in CKD. We identified increased production and elevated blood levels of soluble pro-cachectic factors, including activin A, directly linking experimental and human CKD to skeletal muscle wasting programs. Single-cell sequencing data identified the expression of activin A in specific kidney cell populations of fibroblasts and cells of the juxtaglomerular apparatus. We propose that persistent and increased kidney production of pro-cachectic factors, combined with a lack of kidney clearance, facilitates a vicious kidney/muscle signaling cycle, leading to exacerbated blood accumulation and, thereby, skeletal muscle wasting. Systemic pharmacological blockade of activin A using soluble activin receptor type IIB ligand trap as well as muscle-specific adeno-associated virus-mediated downregulation of its receptor ACVR2A/B prevented muscle wasting in different mouse models of experimental CKD, suggesting that activin A is a key factor in CKD-induced cachexia. In summary, we uncovered a crosstalk between kidney and muscle and propose modulation of activin signaling as a potential therapeutic strategy for skeletal muscle wasting in CKD.

Global, regional and national epidemiology and prevalence of child stunting, wasting and underweight in low- and middle-income countries, 2006-2018.

In 2016, undernutrition, as manifested in childhood stunting, wasting, and underweight were estimated to cause over 1.0 million deaths, 3.9% of years of life lost, and 3.8% of disability-adjusted life years globally. The objective of this study is to estimate the prevalence of undernutrition in low- and middle-income countries (LMICs) using the 2006-2018 cross-sectional nationally representative demographic and health surveys (DHS) data and to explore the sources of regional variations. Anthropometric measurements of children 0-59 months of age from DHS in 62 LMICs worldwide were used. Complete information was available for height-for-age (n = 624,734), weight-for-height (n = 625,230) and weight-for-age (n = 626,130). Random-effects models were fit to estimate the pooled prevalence of stunting, wasting, and underweight. Sources of heterogeneity in the prevalence estimates were explored through subgroup meta-analyses and meta-regression using generalized linear mixed-effects models. Human development index (a country-specific composite index based on life expectancy, literacy, access to education and per capita gross domestic product) and the United Nations region were explored as potential sources of variation in undernutrition. The overall prevalence was 29.1% (95% CI 26.7%, 31.6%) for stunting, 6.3% (95% CI 4.6%, 8.2%) for wasting, and 13.7% (95% CI 10.9%, 16.9%) for underweight. Subgroup analyses suggested that Western Africa, Southern Asia, and Southeastern Asia had a substantially higher estimated prevalence of undernutrition than global average estimates. In multivariable meta-regression, a combination of human development index and United Nations region (a proxy for geographical variation) explained 54%, 56%, and 66% of the variation in stunting, wasting, and underweight prevalence, respectively. Our findings demonstrate that regional, subregional, and country disparities in undernutrition remain, and the residual gaps to close towards achieving the second sustainable development goal-ending undernutrition by 2030.

The clinical relevance and mechanism of skeletal muscle wasting.

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.

Combinatorial Normalization of Liver-Derived Cytokine Pathways Alleviates Hepatic Tumor-Associated Cachexia in Zebrafish.

The role and significance of liver-derived cytokines in cancer-associated cachexia syndrome remain elusive. Here we report that combinatorial counterbalances of the leptin and Igf1 signaling pathways in hepatocellular carcinoma (HCC) models significantly relieves cachexia. Double transgenic zebrafish models of HCC that stably displayed focal lesions, anorexia, and wasting of adipose and muscle tissues were first generated. Knockout of lepr or mc4r from these zebrafish partially restored appetite and exerted moderate or no effect on tissue wasting. However, genetic replenishment of Igf1 in a lepr-mutant background effectively relieved the cachexia-like phenotype without affecting tumor growth. Similarly, administration of napabucasin, a Stat3/Socs3 inhibitor, on the zebrafish HCC model, mammalian cell lines with exogenous IGF1, and two mouse xenograft models restored insulin sensitivity and rescued the wasting of nontumor tissues. Together, these results describe the synergistic impact of leptin and Igf1 normalization in treating certain HCC-associated cachexia as a practical strategy. SIGNIFICANCE: Disruption of leptin signaling with normalized Igf1 expression significantly rescues anorexia, muscle wasting, and adipose wasting in Ras- and Myc-driven zebrafish models of HCC.

The Aryl Hydrocarbon Receptor in Energy Balance: The Road from Dioxin-Induced Wasting Syndrome to Combating Obesity with Ahr Ligands.

The aryl hydrocarbon receptor (AHR) has been studied for over 40 years, yet our understanding of this ligand-activated transcription factor remains incomplete. Each year, novel findings continually force us to rethink the role of the AHR in mammalian biology. The AHR has historically been studied within the context of potent activation via AHR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), with a focus on how the AHR mediates TCDD toxicity. Research has subsequently revealed that the AHR is actively involved in distinct physiological processes ranging from the development of the liver and reproductive organs, to immune system function and wound healing. More recently, the AHR was implicated in the regulation of energy metabolism and is currently being investigated as a potential therapeutic target for obesity. In this review, we re-trace the steps through which the early toxicological studies of TCDD led to the conceptual framework for the AHR as a potential therapeutic target in metabolic disease. We additionally discuss the key discoveries that have been made concerning the role of the AHR in energy metabolism, as well as the current and future directions of the field.

Single Cell ADNP Predictive of Human Muscle Disorders: Mouse Knockdown Results in Muscle Wasting.

Activity-dependent neuroprotective protein (ADNP) mutations are linked with cognitive dysfunctions characterizing the autistic-like ADNP syndrome patients, who also suffer from delayed motor maturation. We thus hypothesized that ADNP is deregulated in versatile myopathies and that local ADNP muscle deficiency results in myopathy, treatable by the ADNP fragment NAP. Here, single-cell transcriptomics identified ADNP as a major constituent of the developing human muscle. ADNP transcript concentrations further predicted multiple human muscle diseases, with concentrations negatively correlated with the ADNP target interacting protein, microtubule end protein 1 (EB1). Reverting back to modeling at the single-cell level of the male mouse transcriptome, Adnp mRNA concentrations age-dependently correlated with motor disease as well as with sexual maturation gene transcripts, while Adnp expressing limb muscle cells significantly decreased with aging. Mouse Adnp heterozygous deficiency exhibited muscle microtubule reduction and myosin light chain (Myl2) deregulation coupled with motor dysfunction. CRISPR knockdown of adult gastrocnemius muscle Adnp in a Cas9 mouse resulted in treadmill (male) and gait (female) dysfunctions that were specifically ameliorated by treatment with the ADNP snippet, microtubule interacting, Myl2-regulating, NAP (CP201). Taken together, our studies provide new hope for personalized diagnosis/therapeutics in versatile myopathies.

Protein energy-wasting associated with nephrotic syndrome - the comparison of metabolic pattern in severe nephrosis to different stages of chronic kidney disease.

BACKGROUND: Nephrotic syndrome (NS) is associated with a hypercatabolic state expressed as an exacerbated degradation of muscle mass. However, the clinical significance of this phenomenon has not yet been investigated. The aim of the study was to evaluate the nutritional status of patients with severe NS (defined as nephrotic range proteinuria with hypoalbuminemia ≤2.5 g/dL) and estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m2 in comparison to patients in different stages of chronic kidney disease (CKD). METHODS: Twenty men with severe NS (NS group) and 40 men without proteinuria similar in term of serum creatinine (control group) were included into the study. A retrospective cohort of 40 men with CKD stage G4 (PreD group) and 20 haemodialysis men (HD group) were added to the analysis after matching for age, height and weight using propensity score matching. The bioimpedance spectroscopy and biochemical nutritional markers were evaluated. RESULTS: Nephrotic patients had a significantly lower lean tissue mass (LTM; p = 0.035) and index (a quotient of LTM over height squared, LTI; p = 0.068), with an expected deficiency of LTM by 3.2 kg, and LTI by 0.9 kg/m2 when compared to the control group. A significant lean tissue deficit (defined as LTI below the lower limit of the reference range by 1.0 kg/m2) was observed in 12.5% of patients in the control group in comparison to 31.7% with advanced CKD (PreD+HD; p = 0.032) and 50% with NS (p = 0.003). NS group presented with higher phosphorus (p = 0.029), uric acid (p = 0.002) and blood urea (p = 0.049) than the control group. Blood urea was strongly negatively correlated with LTM in NS (r = - 0.64, p = 0.002). Nine nephrotic patients (45%) were identified as hypercatabolic based on severe hyperphosphatemia (> 5.0 mg/dL) and/or hyperuricemia (> 8.0 mg/dL), and were characterized by higher blood urea and lower prealbumin, as well as LTM lower by 5.6 kg than in less catabolic individuals. CONCLUSIONS: In term of lean tissue amount, NS group was more similar to advanced CKD than to the control group. We concluded that specific metabolic pattern with elevated phosphorus, uric acid and blood urea, and lean tissue deficiency may be defined as protein-energy wasting associated with nephrotic syndrome (neph-PEW).

Circulating 20S proteasome for assessing protein energy wasting syndrome in hemodialysis patients.

Protein energy wasting (PEW) including muscle atrophy is a common complication in chronic hemodialysis patients. The ubiquitin proteasome system (UPS) is the main proteolytic system causing muscle atrophy in chronic kidney disease and proteasome 20S is the catalytic component of the UPS. Circulating proteasome 20S (c20S proteasome) is present in the blood and its level is related to disease severity and prognosis in several disorders. We hypothesized that c20S proteasome could be related with muscle mass, other PEW criteria and their evolution in hemodialysis patients. Stable hemodialysis patients treated at our center for more than 3 months were followed over 2 years. C20S proteasome assay was performed at baseline. Biological and clinical data were collected, muscle mass was assessed by multi-frequency bio-impedancemetry, and nutritional scores were calculated at baseline, 1 year and 2 years. Hospitalizations and mortality data were collected over the 2 years. Forty-nine patients were included. At baseline, the c20S proteasome level was 0.40[0.26-0.55] µg/ml. Low muscle mass as defined by a lean tissue index (LTI) < 10th in accordance with the International Society of Renal Nutrition and Metabolism guidelines was observed in 36% and PEW in 62%. Increased c20S proteasome levels were related with LTI at baseline (R = 0.43, p = 0.004) and with its 2 year-variation (R = -0.56, p = 0.003). Two-year survival rate was not different between higher and lower c20S proteasome values (78.9 vs 78.4%, p = 0.98 log-rank test). C20S proteasome is not a good marker for assessing nutritional status in hemodialysis patients and predicting patient outcomes.

The profile of lipid metabolites in urine of marmoset wasting syndrome.

Marmoset wasting syndrome (MWS) is clinically characterized by progressive weight loss. Although morbidity and mortality of MWS are relatively high in captive marmosets, its causes remain unknown. Lipid mediators are bioactive metabolites which are produced from polyunsaturated fatty acids, such as arachidonic acid (AA) and eicosapentaenoic acid. These lipid metabolites regulate a wide range of inflammatory responses and they are excreted into the urine. As urinary lipid profiles reflect systemic inflammatory conditions, we comprehensively measured the levels of 141 types of lipid metabolites in the urines obtained from healthy common marmoset (Callithrix jacchus) (N = 7) or marmosets with MWS (N = 7). We found that 41 types of metabolites were detected in all urine samples of both groups. Among them, AA-derived metabolites accounted for 63% (26/41 types) of all detected metabolites. Notably, the levels of AA-derived prostaglandin (PG) E2, PGF2α, thromboxane (TX) B2 and F2-isoprostanes significantly increased in the urine samples of marmosets with MWS. In this study, we found some urinary lipid metabolites which may be involved in the development of MWS. Although the cause of MWS remains unclear, our findings may provide some insight into understanding the mechanisms of development of MWS.

Contemporary stable isotope tracer approaches: Insights into skeletal muscle metabolism in health and disease.

NEW FINDINGS: What is the topic of this review? This review discusses the application of new stable isotope tracer techniques in understanding the control of skeletal muscle mass. What advances does it highlight? This review highlights current advances in stable isotope tracer techniques through their combination with high-throughput proteomics technologies. ABSTRACT: Beyond its primary locomotory and key structural functions, skeletal muscle provides additional vital roles for maintenance of metabolic health, acting as a storage point for glucose and intramuscular lipids for energy production, alongside being the largest reservoir for amino acids in the body. Therefore, maintenance of muscle mass is key to the promotion of health and well-being across the lifespan and in several disease states. As such, when skeletal muscle is lost, in either clinical (cancer, organ failure etc.) or non-clinical (ageing, inactivity) situations, there are potentially devastating consequences attached, with robust links existing between muscle mass loss and mortality. Great efforts are being made to reverse or slow muscle mass declines in health and disease, through combinations of lifestyle changes and nutritional and/or pharmaceutical intervention. However, despite this comprehensive research effort, the underlying metabolic and molecular mechanisms have yet to be defined properly. However, with the rapid acceleration of analytical developments over recent years, the application of stable isotope tracers to the study of human muscle metabolism is providing unique insights into the mechanisms controlling skeletal muscle loss and allowing more targeted therapeutic strategies to be developed. The aim of this review is to highlight the technical breakthroughs in our understanding of muscle wasting in health and disease and how future directions and developments incorporating 'omics' with stable isotope tracers will allow for a more personalized and stratified therapeutic approach.

Deletion of metal transporter Zip14 (Slc39a14) produces skeletal muscle wasting, endotoxemia, Mef2c activation and induction of miR-675 and Hspb7.

Skeletal muscle represents the largest pool of body zinc, however, little is known about muscle zinc homeostasis or muscle-specific zinc functions. Zip14 (Slc39a14) was the most highly expressed zinc transporter in skeletal muscle of mice in response to LPS-induced inflammation. We compared metabolic parameters of skeletal muscle from global Zip14 knockout (KO) and wild-type mice (WT). At basal steady state Zip14 KO mice exhibited a phenotype that included muscle wasting and metabolic endotoxemia. Microarray and qPCR analysis of gastrocnemius muscle RNA revealed that ablation of Zip14 produced increased muscle p-Mef2c, Hspb7 and miR-675-5p expression and increased p38 activation. ChIP assays showed enhanced binding of NF-[Formula: see text] to the Mef2c promoter. In contrast, LPS-induced systemic inflammation enhanced Zip14-dependent zinc uptake by muscle, increased expression of Atrogin1 and MuRF1 and markedly reduced MyoD. These signatures of muscle atrophy and cachexia were not influenced by Zip14 ablation, however. LPS-induced miR-675-3p and -5p expression was Zip14-dependent. Collectively, these results with an integrative model are consistent with a Zip14 function in skeletal muscle at steady state that supports myogenesis through suppression of metabolic endotoxemia and that Zip14 ablation coincides with sustained activity of phosphorylated components of signaling pathways including p-Mef2c, which causes Hspb7-dependent muscle wasting.

MEF2c-Dependent Downregulation of Myocilin Mediates Cancer-Induced Muscle Wasting and Associates with Cachexia in Patients with Cancer.

Skeletal muscle wasting is a devastating consequence of cancer that contributes to increased complications and poor survival, but is not well understood at the molecular level. Herein, we investigated the role of Myocilin (Myoc), a skeletal muscle hypertrophy-promoting protein that we showed is downregulated in multiple mouse models of cancer cachexia. Loss of Myoc alone was sufficient to induce phenotypes identified in mouse models of cancer cachexia, including muscle fiber atrophy, sarcolemmal fragility, and impaired muscle regeneration. By 18 months of age, mice deficient in Myoc showed significant skeletal muscle remodeling, characterized by increased fat and collagen deposition compared with wild-type mice, thus also supporting Myoc as a regulator of muscle quality. In cancer cachexia models, maintaining skeletal muscle expression of Myoc significantly attenuated muscle loss, while mice lacking Myoc showed enhanced muscle wasting. Furthermore, we identified the myocyte enhancer factor 2 C (MEF2C) transcription factor as a key upstream activator of Myoc whose gain of function significantly deterred cancer-induced muscle wasting and dysfunction in a preclinical model of pancreatic ductal adenocarcinoma (PDAC). Finally, compared with noncancer control patients, MYOC was significantly reduced in skeletal muscle of patients with PDAC defined as cachectic and correlated with MEF2c. These data therefore identify disruptions in MEF2c-dependent transcription of Myoc as a novel mechanism of cancer-associated muscle wasting that is similarly disrupted in muscle of patients with cachectic cancer. SIGNIFICANCE: This work identifies a novel transcriptional mechanism that mediates skeletal muscle wasting in murine models of cancer cachexia that is disrupted in skeletal muscle of patients with cancer exhibiting cachexia.

Weaning and stunting affect nitrogen and carbon stable isotope natural abundances in the hair of young children.

Natural abundances of stable nitrogen and carbon isotopes (δ15N and δ13C) can vary with both dietary intake and metabolic (specifically catabolic) state. In low-income countries, weaning is a period of dietary transition from milk to plant-based foods and a high-risk period for malnutrition. We explored how diet and malnutrition impact hair δ15N and δ13C in young children by an observational, cross-sectional study in Cox's Bazar District, Bangladesh [255 children, 6-59 months with 19.6% wasted (7.1% severely) and 36% stunted (9.8% severely)]. Hair δ15N and δ13C exhibited exponential decreases with age, with the loss of one trophic level (3.3‰ and 0.8‰, respectively) from 6 to 48 months, which we associate with the shift from exclusive breastfeeding to complete weaning. After adjustment for age and breastfeeding status, hair isotopic values were unaffected by wasting but lower in severe stunting (-0.45‰ to -0.6‰, P < 0.01). In this population of young children, whose isotopic values in hair primarily depended on age, we failed to observe any effect of wasting, likely due to opposite, compensating effects between dietary and metabolic changes involved. In contrast, we evidenced low δ15N and δ13C values in severely stunted children that likely indicate chronic exposure to diets low in animal products.

Dysregulation of Mitochondrial Ca2+ Uptake and Sarcolemma Repair Underlie Muscle Weakness and Wasting in Patients and Mice Lacking MICU1.

Muscle function is regulated by Ca2+, which mediates excitation-contraction coupling, energy metabolism, adaptation to exercise, and sarcolemmal repair. Several of these actions rely on Ca2+ delivery to the mitochondrial matrix via the mitochondrial Ca2+ uniporter, the pore of which is formed by mitochondrial calcium uniporter (MCU). MCU's gatekeeping and cooperative activation are controlled by MICU1. Loss-of-protein mutation in MICU1 causes a neuromuscular disease. To determine the mechanisms underlying the muscle impairments, we used MICU1 patient cells and skeletal muscle-specific MICU1 knockout mice. Both these models show a lower threshold for MCU-mediated Ca2+ uptake. Lack of MICU1 is associated with impaired mitochondrial Ca2+ uptake during excitation-contraction, aerobic metabolism impairment, muscle weakness, fatigue, and myofiber damage during physical activity. MICU1 deficit compromises mitochondrial Ca2+ uptake during sarcolemmal injury, which causes ineffective repair of the damaged myofibers. Thus, dysregulation of mitochondrial Ca2+ uptake hampers myofiber contractile function, likely through energy metabolism and membrane repair.

Systemic inflammation in colorectal cancer: Underlying factors, effects, and prognostic significance.

Systemic inflammation is a marker of poor prognosis preoperatively present in around 20%-40% of colorectal cancer patients. The hallmarks of systemic inflammation include an increased production of proinflammatory cytokines and acute phase proteins that enter the circulation. While the low-level systemic inflammation is often clinically silent, its consequences are many and may ultimately lead to chronic cancer-associated wasting, cachexia. In this review, we discuss the pathogenesis of cancer-related systemic inflammation, explore the role of systemic inflammation in promoting cancer growth, escaping antitumor defense, and shifting metabolic pathways, and how these changes are related to less favorable outcome.

[Nutrition in chronic kidney disease]. / Nutrición en insuficiencia renal crónica.

INTRODUCTION: Chronic kidney disease patients often also present protein-calorie malnutrition, and it is a powerful predictor of morbidity and mortality. In this article, causes and management are shown, highlighting oral and parenteral nutritional supplementation, especially during dialysis process.

INTRODUCCIÓN: Los pacientes con insuficiencia renal crónica presentan frecuentemente malnutrición calórico-proteica, y esta situación es un predictor de morbilidad y mortalidad. En este artículo, se resumen las causas de la desnutrición y las diferentes aproximaciones terapéuticas para revertirla, entre las que se incluyen la suplementación nutricional oral o parenteral, especialmente durante la diálisis.