Dietary Amino Acids and Immunonutrition Supplementation in Cancer-Induced Skeletal Muscle Mass Depletion: A Mini-Review

2020 ◽  
Vol 26 (9) ◽  
pp. 970-978 ◽  
Author(s):  
Jéssika D.P. Soares ◽  
Scott L. Howell ◽  
Filipe J. Teixeira ◽  
Gustavo D. Pimentel
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Cancer Patients ◽  
Muscle Mass ◽  
Muscle Protein ◽  
Nutritional Interventions ◽  
Dietary Amino Acids ◽  
Mass Depletion ◽  
Methyl Butyrate ◽  
Regulate Protein

Cancer patients display systemic inflammation, which leads to an increase in protein catabolism, thus promoting the release of free amino acids to further support metabolism and remodelling of muscle proteins. Inflammation associated with tumor growth leads to malnutrition, a factor that increases the risk of developing cachexia. With cancer-induced cachexia, nutritional interventions have gained traction as a preventative method to manage this condition. Currently, cancer consensus recommendations suggest a protein intake above 1.0 g/kg.day-1 up to 2.0 g/k.day-1 for cancer patients, although an ideal amount for some amino acids in isolation has yet to be determined. Due to controversy in the literature regarding the benefits of the biochemical mechanisms of various muscle mass supplements, such as L-leucine (including whey protein and BCAA), β-hydroxy-beta-methyl butyrate (HMβ), arginine, glutamine and creatine, several studies have carefully examined their effects. L-leucine and its derivatives appear to regulate protein synthesis by direct or indirect activation of the mTORC1 pool of kinases, further promoting muscle protein balance. Arginine and glutamine may act by reducing inflammation and infection progression, thus promoting improvements in food intake. Creatine exerts anabolic activity, acting as an immediate energy substrate to support muscle contraction further increasing lean mass, mainly due to greater water uptake by the muscle. In this narrative review, we highlighted the main findings regarding protein consumption and amino acids to mitigate cancer-induced skeletal muscle depletion.

scholarly journals Impact of a ketogenic diet intervention during radiotherapy on body composition: III. An interim analysis of the KETOCOMP study

2018 ◽  
Author(s):  
Rainer J. Klement ◽  
Gabriele Schäfert ◽  
Reinhart A. Sweeney
Keyword(s):  
Breast Cancer ◽  
Skeletal Muscle ◽  
Amino Acids ◽  
Rectal Cancer ◽  
Body Composition ◽  
Cancer Patients ◽  
Muscle Mass ◽  
Skeletal Muscle Mass ◽  
Essential Amino Acids ◽  
Ketogenic Diets

AbstractBackgroundKetogenic therapy (KT) in the form of ketogenic diets (KDs) and/or supplements that induce nutritional ketosis have gained interest as a complementary treatment for cancer patients. Besides putative anti-tumor effects, preclinical and preliminary clinical data indicate that KT could induce favorable changes in body composition of the tumor bearing host. Here we present first results of our ongoing KETOCOMP study (NCT02516501) study concerning body composition changes among rectal, breast and head & neck cancer (HNC) patients who underwent concurrent KT during standard-of-care radiotherapy (RT).MethodsEligible patients were assigned to one of three groups: (i) a standard diet group; (ii) a ketogenic breakfast group taking 50-250 ml of a medium-chain triglyceride (MCT) drink plus 10 g essential amino acids in the morning of RT days; (iii) a complete KD group supplemented with 10 g essential amino acids on RT days. Body composition was to be measured prior to and weekly during RT using 8-electrode bioimpedance analysis. Longitudinal data were analyzed using mixed effects linear regression.ResultsA total of 17 patients underwent KT during RT thus far (rectal cancer: n=6; HNC: n=6; breast cancer: n=5). All patients consuming a KD (n=14) reached nutritional ketosis and finished the study protocol with only minor problems reported. Compared to control subjects, the ketogenic intervention in rectal and breast cancer patients was significantly associated with a decline in fat mass over time (−0.3 and −0.5 kg/week, respectively), with no significant changes in skeletal muscle mass. In HNC patients, concurrent chemotherapy was the strongest predictor of body weight, fat free and skeletal muscle mass decline during radiotherapy, while KT showed significant opposite associations. Rectal cancer patients who underwent KT during neoadjuvant RT had significantly better tumor response at the time of surgery as assessed by the Dworak regression grade (median 3 versus 2, p=0.04483).ConclusionsWhile sample sizes are still small our results already indicate some significant favorable effects of KT on body composition. These as well as a putative radiosensitizing effect on rectal tumor cells need to be confirmed once the final analysis of our study becomes possible.

scholarly journals More than just a garbage can: emerging roles of the lysosome as an anabolic organelle in skeletal muscle

2020 ◽  
Vol 319 (3) ◽  
pp. C561-C568
Author(s):  
Sidney Abou Sawan ◽  
Michael Mazzulla ◽  
Daniel R. Moore ◽  
Nathan Hodson
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Intracellular Signaling ◽  
Muscle Protein ◽  
Future Research ◽  
Dietary Amino Acids ◽  
Lysosome Biogenesis ◽  
Transcription Factor Eb ◽  
Mtorc1 Activation

Skeletal muscle is a highly plastic tissue capable of remodeling in response to a range of physiological stimuli, including nutrients and exercise. Historically, the lysosome has been considered an essentially catabolic organelle contributing to autophagy, phagocytosis, and exo-/endocytosis in skeletal muscle. However, recent evidence has emerged of several anabolic roles for the lysosome, including the requirement for autophagy in skeletal muscle mass maintenance, the discovery of the lysosome as an intracellular signaling hub for mechanistic target of rapamycin complex 1 (mTORC1) activation, and the importance of transcription factor EB/lysosomal biogenesis-related signaling in the regulation of mTORC1-mediated protein synthesis. We, therefore, propose that the lysosome is an understudied organelle with the potential to underpin the skeletal muscle adaptive response to anabolic stimuli. Within this review, we describe the molecular regulation of lysosome biogenesis and detail the emerging anabolic roles of the lysosome in skeletal muscle with particular emphasis on how these roles may mediate adaptations to chronic resistance exercise. Furthermore, given the well-established role of amino acids to support muscle protein remodeling, we describe how dietary proteins “labeled” with stable isotopes could provide a complementary research tool to better understand how lysosomal biogenesis, autophagy regulation, and/or mTORC1-lysosomal repositioning can mediate the intracellular usage of dietary amino acids in response to anabolic stimuli. Finally, we provide avenues for future research with the aim of elucidating how the regulation of this important organelle could mediate skeletal muscle anabolism.

scholarly journals Biochemical approaches for nutritional support of skeletal muscle protein metabolism during sepsis

2004 ◽  
Vol 17 (1) ◽  
pp. 77-88 ◽  
Author(s):  
Thomas C. Vary ◽  
Christopher J. Lynch
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Metabolic Response ◽  
Muscle Protein ◽  
The Body ◽  
Integrated Analysis ◽  
Skeletal Muscle Protein ◽  
Catabolic State ◽  
N Metabolism ◽  
Induced Defects

Sepsis initiates a unique series of modifications in the homeostasis of N metabolism and profoundly alters the integration of inter-organ cooperatively in the overall N and energy economy of the host. The net effect of these alterations is an overall N catabolic state, which seriously compromises recovery and is semi-refractory to treatment with current therapies. These alterations lead to a functional redistribution of N (amino acids and proteins) and substrate metabolism among injured tissues and major body organs. The redistribution of amino acids and proteins results in a quantitative reordering of the usual pathways of C and N flow within and among regions of the body with a resultant depletion of the required substrates and cofactors in important organs. The metabolic response to sepsis is a highly integrated, complex series of reactions. To understand the regulation of the response to sepsis, a comprehensive, integrated analysis of the fundamental physiological relationships of key metabolic pathways and mechanisms in sepsis is essential. The catabolism of skeletal muscles, which is manifested by an increase in protein degradation and a decrease in synthesis, persists despite state-of-the-art nutritional care. Much effort has focused on the modulation of the overall amount of nutrients given to septic patients in a hope to improve efficiencies in utilisation and N economies, rather than the support of specific end-organ targets. The present review examines current understanding of the processes affected by sepsis and testable means to circumvent the sepsis-induced defects in protein synthesis in skeletal muscle through increasing provision of amino acids (leucine, glutamine, or arginine) that in turn act as nutrient signals to regulate a number of cellular processes.

Growth hormone acutely stimulates forearm muscle protein synthesis in normal humans

1991 ◽  
Vol 260 (3) ◽  
pp. E499-E504 ◽  
Author(s):  
D. A. Fryburg ◽  
R. A. Gelfand ◽  
E. J. Barrett
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Growth Hormone ◽  
Protein Synthesis ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Skeletal Muscle Protein ◽  
Skeletal Muscle Protein Synthesis ◽  
Igf I ◽  
Normal Humans

The short-term effects of growth hormone (GH) on skeletal muscle protein synthesis and degradation in normal humans are unknown. We studied seven postabsorptive healthy men (age 18-23 yr) who received GH (0.014 micrograms.kg-1.min-1) via intrabrachial artery infusion for 6 h. The effects of GH on forearm amino acid and glucose balances and on forearm amino acid kinetics [( 3H]Phe and [14C]Leu) were determined after 3 and 6 h of the GH infusion. Forearm deep vein GH rose to 35 +/- 6 ng/ml in response to GH, whereas systemic levels of GH, insulin, and insulin-like growth factor I (IGF-I) were unchanged. Forearm glucose uptake did not change during the study. After 6 h, GH suppressed forearm net release (3 vs. 6 h) of Phe (P less than 0.05), Leu (P less than 0.01), total branched-chain amino acids (P less than 0.025), and essential neutral amino acids (0.05 less than P less than 0.1). The effect on the net balance of Phe and Leu was due to an increase in the tissue uptake for Phe (71%, P less than 0.05) and Leu (37%, P less than 0.005) in the absence of any significant change in release of Phe or Leu from tissue. In the absence of any change in systemic GH, IGF-I, or insulin, these findings suggest that locally infused GH stimulates skeletal muscle protein synthesis. These findings have important physiological implications for both the role of daily GH pulses and the mechanisms through which GH can promote protein anabolism.

scholarly journals Growth Hormone, Alone and in Combination With Insulin, Increases Whole Body and Skeletal Muscle Protein Kinetics in Cancer Patients After Surgery

1999 ◽  
Vol 229 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Russell S. Berman ◽  
Lawrence E. Harrison ◽  
David B. Pearlstone ◽  
Michael Burt ◽  
Murray F. Brennan
Keyword(s):  
Skeletal Muscle ◽  
Growth Hormone ◽  
Cancer Patients ◽  
Muscle Protein ◽  
Whole Body ◽  
Skeletal Muscle Protein ◽  
Protein Kinetics

scholarly journals Immunohistochemical phenotyping of T cells, granulocytes, and phagocytes in the muscle of cancer patients: association with radiologically defined muscle mass and gene expression

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ana Anoveros-Barrera ◽  
Amritpal S. Bhullar ◽  
Cynthia Stretch ◽  
Abha R. Dunichand-Hoedl ◽  
Karen J. B. Martins ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
T Cells ◽  
Cancer Patients ◽  
Muscle Mass ◽  
Muscle Fiber ◽  
Cd8 T Cells ◽  
Immune Cell ◽  
Cell Populations ◽  
Cd4 Cells ◽  
Gene Correlation

Abstract Background Inflammation is a recognized contributor to muscle wasting. Research in injury and myopathy suggests that interactions between the skeletal muscle and immune cells confer a pro-inflammatory environment that influences muscle loss through several mechanisms; however, this has not been explored in the cancer setting. This study investigated the local immune environment of the muscle by identifying the phenotype of immune cell populations in the muscle and their relationship to muscle mass in cancer patients. Methods Intraoperative muscle biopsies were collected from cancer patients (n = 30, 91% gastrointestinal malignancies). Muscle mass was assessed histologically (muscle fiber cross-sectional area, CSA; μm2) and radiologically (lumbar skeletal muscle index, SMI; cm2/m2 by computed tomography, CT). T cells (CD4 and CD8) and granulocytes/phagocytes (CD11b, CD14, and CD15) were assessed by immunohistochemistry. Microarray analysis was conducted in the muscle of a second cancer patient cohort. Results T cells (CD3+), granulocytes/phagocytes (CD11b+), and CD3−CD4+ cells were identified. Muscle fiber CSA (μm2) was positively correlated (Spearman’s r = > 0.45; p = < 0.05) with the total number of T cells, CD4, and CD8 T cells and granulocytes/phagocytes. In addition, patients with the smallest SMI exhibited fewer CD8 T cells within their muscle. Consistent with this, further exploration with gene correlation analyses suggests that the presence of CD8 T cells is negatively associated (Pearson’s r = ≥ 0.5; p = <0.0001) with key genes within muscle catabolic pathways for signaling (ACVR2B), ubiquitin proteasome (FOXO4, TRIM63, FBXO32, MUL1, UBC, UBB, UBE2L3), and apoptosis/autophagy (CASP8, BECN1, ATG13, SIVA1). Conclusion The skeletal muscle immune environment of cancer patients is comprised of immune cell populations from the adaptive and innate immunity. Correlations of T cells, granulocyte/phagocytes, and CD3−CD4+ cells with muscle mass measurements indicate a positive relationship between immune cell numbers and muscle mass status in cancer patients. Further exploration with gene correlation analyses suggests that the presence of CD8 T cells is negatively correlated with components of muscle catabolism.

scholarly journals Knockdown of the E3 ubiquitin ligase UBR5 and its role in skeletal muscle anabolism

2021 ◽  
Vol 320 (1) ◽  
pp. C45-C56
Author(s):  
David C. Hughes ◽  
Daniel C. Turner ◽  
Leslie M. Baehr ◽  
Robert A. Seaborne ◽  
Mark Viggars ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Ubiquitin Ligase ◽  
Fluorescent Protein ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Tibialis Anterior Muscle ◽  
E3 Ubiquitin Ligase ◽  
Skeletal Muscle Atrophy ◽  
The Impact

UBR5 is an E3 ubiquitin ligase positively associated with anabolism, hypertrophy, and recovery from atrophy in skeletal muscle. The precise mechanisms underpinning UBR5’s role in the regulation of skeletal muscle mass remain unknown. The present study aimed to elucidate these mechanisms by silencing the UBR5 gene in vivo. To achieve this aim, we electroporated a UBR5-RNAi plasmid into mouse tibialis anterior muscle to investigate the impact of reduced UBR5 on anabolic signaling MEK/ERK/p90RSK and Akt/GSK3β/p70S6K/4E-BP1/rpS6 pathways. Seven days after UBR5 RNAi electroporation, although reductions in overall muscle mass were not detected, the mean cross-sectional area (CSA) of green fluorescent protein (GFP)-positive fibers were reduced (−9.5%) and the number of large fibers were lower versus the control. Importantly, UBR5-RNAi significantly reduced total RNA, muscle protein synthesis, ERK1/2, Akt, and GSK3β activity. Although p90RSK phosphorylation significantly increased, total p90RSK protein levels demonstrated a 45% reduction with UBR5-RNAi. Finally, these early events after 7 days of UBR5 knockdown culminated in significant reductions in muscle mass (−4.6%) and larger reductions in fiber CSA (−18.5%) after 30 days. This was associated with increased levels of phosphatase PP2Ac and inappropriate chronic elevation of p70S6K and rpS6 between 7 and 30 days, as well as corresponding reductions in eIF4e. This study demonstrates that UBR5 plays an important role in anabolism/hypertrophy, whereby knockdown of UBR5 culminates in skeletal muscle atrophy.

scholarly journals Higher skeletal muscle protein synthesis and lower breakdown after chemotherapy in cachectic mice

2001 ◽  
Vol 281 (1) ◽  
pp. R133-R139 ◽  
Author(s):  
S. E. Samuels ◽  
A. L. Knowles ◽  
T. Tilignac ◽  
E. Debiton ◽  
J. C. Madelmont ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Muscle Mass ◽  
Skeletal Muscle Mass ◽  
Cancer Cachexia ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Human Condition ◽  
Skeletal Muscle Protein ◽  
Tumor Bearing

The influence of cancer cachexia and chemotherapy and subsequent recovery of skeletal muscle protein mass and turnover was investigated in mice. Cancer cachexia was induced using colon 26 adenocarcinoma, which is characteristic of the human condition, and can be cured with 100% efficacy using an experimental nitrosourea, cystemustine (C6H12CIN3O4S). Reduced food intake was not a factor in these studies. Three days after cachexia began, healthy and tumor-bearing mice were given a single intraperitoneal injection of cystemustine (20 mg/kg). Skeletal muscle mass in tumor-bearing mice was 41% lower ( P < 0.05) than in healthy mice 2 wk after cachexia began. Skeletal muscle wasting was mediated initially by decreased protein synthesis (−38%; P < 0.05) and increased degradation (+131%; P < 0.05); later wasting resulted solely from decreased synthesis (∼−54 to −69%; P < 0.05). Acute cytotoxicity of chemotherapy did not appear to have an important effect on skeletal muscle protein metabolism in either healthy or tumor-bearing mice. Recovery began 2 days after treatment; skeletal muscle mass was only 11% lower than in healthy mice 11 days after chemotherapy. Recovery of skeletal muscle mass was affected initially by decreased protein degradation (−80%; P < 0.05) and later by increased protein synthesis (+46 to +73%; P < 0.05) in cured compared with healthy mice. This study showed that skeletal muscle wasted from cancer cachexia and after chemotherapeutic treatment is able to generate a strong anabolic response by making powerful changes to protein synthesis and degradation.

scholarly journals Staging of nutrition disorders in non‐small‐cell lung cancer patients: utility of skeletal muscle mass assessment

2019 ◽  
Vol 10 (4) ◽  
pp. 782-793 ◽  
Author(s):  
Sami Antoun ◽  
Hugues Morel ◽  
Pierre‐Jean Souquet ◽  
Veerle Surmont ◽  
David Planchard ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Skeletal Muscle ◽  
Small Cell Lung Cancer ◽  
Cancer Patients ◽  
Muscle Mass ◽  
Skeletal Muscle Mass ◽  
Small Cell ◽  
Small Cell Lung ◽  
Lung Cancer Patients ◽  
Nutrition Disorders

scholarly journals Myofibrillar Protein Abundance and Anabolic Signaling in Myotubes Depleted of E1 Alpha Subunit of Branched-Chain Ketoacid Dehydrogenase Complex

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 642-642
Author(s):  
Glory Madu ◽  
Olasunkanmi Adegoke
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Protein Content ◽  
Muscle Protein ◽  
Essential Amino Acids ◽  
Myofibrillar Protein ◽  
L6 Myotubes ◽  
Branched Chain ◽  
Ketoacid Dehydrogenase

Abstract Objectives Branched-chain amino acids (BCAAs) are essential amino acids that are crucial for skeletal muscle anabolism. Thus, alterations in their levels are associated with muscle atrophic diseases such as cancer, chronic inflammatory and neurological disorders. Others have linked impairments in BCAA metabolism to the development of insulin resistance and its sequelae. Compared to the effects of theses amino acids, much less is known on how impairment in BCAA catabolism affects skeletal muscle. BCAA catabolism starts with the reversible transamination by the mitochondrial enzyme branched-chain aminotransferase 2 (BCAT2). This is followed by the irreversible carboxylation, catalyzed by branched-chain ketoacid dehydrogenase (BCKD) complex. We have shown that BCAT2 and BCKD are essential for the differentiation of skeletal myoblasts into myotubes. Here, we investigated the effect of depletion of BCAT2 or of E1a subunit of BCKD in differentiated myotubes. Methods On day 4 of differentiation, L6 myotubes were transfected with the following siRNA oligonucleotides: scrambled (control), BCAT2, or E1a subunit of BCKD. Results Forty-eight hours after transfection, compared to control or BCAT2 siRNA group, we observed improved myotube structure in BCKD-depleted cells. BCKD depletion augmented myofibrillar protein levels: myosin heavy chain (MHC, 2-fold) and tropomyosin (4-fold), P &lt; 0.05, n = 3. To further analyze the increase in myofibrillar protein content, we examined signaling through mTORC1 (mechanistic target of rapamycin complex 1), a vital complex necessary for skeletal muscle anabolism. BCKD depletion increased the phosphorylation of mTORC1 upstream activator AKT (52%, P &lt; 0.05, n = 3), and of mTORC1 downstream substrates by 25%-86%, consistent with the increase in myofibrillar proteins. Finally, in myotubes treated with the catabolic cytokine (tumor necrosis factor-a), BCKD depletion tended to increase the abundance of tropomyosin (a myofibrillar protein). Conclusions We showed that depletion of BCKD enhanced myofibrillar protein content and anabolic signaling.  If these data are confirmed in vivo, development of dietary and other interventions that target BCKD abundance or functions may promote muscle protein anabolism in individuals with muscle wasting conditions. Funding Sources MHRC, NSERC York U.

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