The impact of catecholamines on skeletal muscle following massive burns: Friend or foe?

AbstractImpaired skeletal muscle quality is a major risk factor for adverse outcomes in acute respiratory failure. However, conventional methods for skeletal muscle assessment are inapplicable in the critical care setting. This study aimed to determine the prognostic value of computed tomography (CT) fatty muscle fraction (FMF) as a biomarker of muscle quality in patients undergoing extracorporeal membrane oxygenation (ECMO). To calculate FMF, paraspinal skeletal muscle area was obtained from clinical CT and separated into areas of fatty and lean muscle based on densitometric thresholds. The cohort was binarized according to median FMF. Patients with high FMF displayed significantly increased 1-year mortality (72.7% versus 55.8%, P = 0.036) on Kaplan–Meier analysis. A multivariable logistic regression model was built to test the impact of FMF on outcome. FMF was identified as a significant predictor of 1-year mortality (hazard ratio per percent FMF, 1.017 [95% confidence interval, 1.002–1.033]; P = 0.031), independent of anthropometric characteristics, Charlson Comorbidity Index, Simplified Acute Physiology Score, Respiratory Extracorporeal Membrane Oxygenation Survival Prediction Score, and duration of ECMO support. To conclude, FMF predicted 1-year mortality independently of established clinical prognosticators in ECMO patients and may have the potential to become a new muscle quality imaging biomarker, which is available from clinical CT.

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The Orphan Nuclear Receptor 4A1: A Potential New Therapeutic Target for Metabolic Diseases

Journal of Diabetes Research ◽

10.1155/2018/9363461 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 5

Author(s):

Lei Zhang ◽

Qun Wang ◽

Wen Liu ◽

Fangyan Liu ◽

Ailing Ji ◽

...

Keyword(s):

Skeletal Muscle ◽

Lipid Metabolism ◽

Nuclear Receptor ◽

Metabolic Diseases ◽

Early Response ◽

Orphan Receptor ◽

Special Focus ◽

Orphan Nuclear Receptor ◽

Physiological Functions ◽

The Impact

Orphan nuclear receptor 4A1 (NR4A1) is a transcriptional factor of the nuclear orphan receptor (NR4A) superfamily that has sparked interest across different research fields in recent years. Several studies have demonstrated that ligand-independent NR4A1 is an immediate-early response gene and the protein product is rapidly induced by a variety of stimuli. Hyperfunction or dysfunction of NR4A1 is implicated in various metabolic processes, including carbohydrate metabolism, lipid metabolism, and energy balance, in major metabolic tissues, such as liver, skeletal muscle, pancreatic tissues, and adipose tissues. No endogenous ligands for NR4A1 have been identified, but numerous compounds that bind and activate or inactivate nuclear NR4A1 or induce cytoplasmic localization of NR4A1 have been identified. This review summarizes recent advances in our understanding of the molecular biology and physiological functions of NR4A1. And we focus on the physiological functions of NR4A1 receptor to the development of the metabolic diseases, with a special focus on the impact on carbohydrate and lipid metabolism in skeletal muscle, liver, adipose tissue, and islet.

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Extensive inflammatory cell infiltration in human skeletal muscle in response to an ultraendurance exercise bout in experienced athletes

Journal of Applied Physiology ◽

10.1152/japplphysiol.01538.2011 ◽

2013 ◽

Vol 114 (1) ◽

pp. 66-72 ◽

Cited By ~ 33

Author(s):

Peter Marklund ◽

C. Mikael Mattsson ◽

Britta Wåhlin-Larsson ◽

Elodie Ponsot ◽

Björn Lindvall ◽

...

Keyword(s):

Skeletal Muscle ◽

Mhc Class I ◽

Inflammatory Cell ◽

Exercise Bout ◽

Inflammatory Cell Infiltration ◽

Class I ◽

Cell Infiltration ◽

Class I Mhc ◽

Inflammatory Reactions ◽

The Impact

The impact of a 24-h ultraendurance exercise bout on systemic and local muscle inflammatory reactions was investigated in nine experienced athletes. Blood and muscle biopsies were collected before (Pre), immediately after the exercise bout (Post), and after 28 h of recovery (Post28). Circulating blood levels of leukocytes, creatine kinase (CK), C-reactive protein (CRP), and selected inflammatory cytokines were assessed together with the evaluation of the occurrence of inflammatory cells (CD3+, CD8+, CD68+) and the expression of major histocompatibility complex class I (MHC class I) in skeletal muscle. An extensive inflammatory cell infiltration occurred in all athletes, and the number of CD3+, CD8+, and CD68+ cells were two- to threefold higher at Post28 compared with Pre ( P < 0.05). The inflammatory cell infiltration was associated with a significant increase in the expression of MHC class I in muscle fibers. There was a significant increase in blood leukocyte count, IL-6, IL-8, CRP, and CK at Post. At Post28, total leukocytes, IL-6, and CK had declined, whereas IL-8 and CRP continued to increase. Increases in IL-1β and TNF-α were not significant. There were no significant associations between the magnitude of the systemic and local muscle inflammatory reactions. Signs of muscle degenerative and regenerative events were observed in all athletes with various degrees of severity and were not affected by the 24-h ultraendurance exercise bout. In conclusion, a low-intensity but very prolonged single-endurance exercise bout can generate a strong inflammatory cell infiltration in skeletal muscle of well-trained experienced ultraendurance athletes, and the amplitude of the local reaction is not proportional to the systemic inflammatory response.

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Antecubital Vein Cannula Position Impacts Assessment of Forearm Glucose Uptake During an Oral Glucose Challenge in Healthy Volunteers

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/a-1275-4038 ◽

2020 ◽

Author(s):

Cécile Bétry ◽

Aline V. Nixon ◽

Paul L. Greenhaff ◽

Elizabeth J. Simpson

Keyword(s):

Skeletal Muscle ◽

Blood Glucose ◽

Glucose Uptake ◽

Venous Blood ◽

Whole Body ◽

Oral Glucose ◽

Antecubital Vein ◽

Glucose Challenge ◽

The Impact

Abstract Introduction Skeletal muscle is a major site for whole-body glucose disposal, and determination of skeletal muscle glucose uptake is an important metabolic measurement, particularly in research focussed on interventions that impact muscle insulin sensitivity. Calculating arterial-venous difference in blood glucose can be used as an indirect measure for assessing glucose uptake. However, the possibility of multiple tissues contributing to the composition of venous blood, and the differential in glucose uptake kinetics between tissue types, suggests that sampling from different vein sites could influence the estimation of glucose uptake. This study aimed to determine the impact of venous cannula position on calculated forearm glucose uptake following an oral glucose challenge in resting and post-exercise states. Materials and Methods In 9 young, lean, males, the impact of sampling blood from two antecubital vein positions; the perforating vein (‘perforating’ visit) and, at the bifurcation of superficial and perforating veins (‘bifurcation’ visit), was assessed. Brachial artery blood flow and arterialised-venous and venous blood glucose concentrations were measured in 3 physiological states; resting-fasted, resting-fed, and fed following intermittent forearm muscle contraction (fed-exercise). Results Following glucose ingestion, forearm glucose uptake area under the curve was greater for the ‘perforating’ than for the ‘bifurcation’ visit in the resting-fed (5.92±1.56 vs. 3.69±1.35 mmol/60 min, P<0.01) and fed-exercise (17.38±7.73 vs. 11.40±7.31 mmol/75 min, P<0.05) states. Discussion Antecubital vein cannula position impacts calculated postprandial forearm glucose uptake. These findings have implications for longitudinal intervention studies where serial determination of forearm glucose uptake is required.

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Branched-chain amino acid metabolism is regulated by ERRα in primary human myotubes and is further impaired by glucose loading in type 2 diabetes

Diabetologia ◽

10.1007/s00125-021-05481-9 ◽

2021 ◽

Author(s):

Rasmus J. O. Sjögren ◽

David Rizo-Roca ◽

Alexander V. Chibalin ◽

Elin Chorell ◽

Regula Furrer ◽

...

Keyword(s):

Type 2 Diabetes ◽

Skeletal Muscle ◽

Amino Acid ◽

Glucose Homeostasis ◽

Gene Set ◽

Branched Chain Amino Acid ◽

Human Myotubes ◽

Branched Chain ◽

The Impact

Abstract Aims/hypothesis Increased levels of branched-chain amino acids (BCAAs) are associated with type 2 diabetes pathogenesis. However, most metabolomic studies are limited to an analysis of plasma metabolites under fasting conditions, rather than the dynamic shift in response to a metabolic challenge. Moreover, metabolomic profiles of peripheral tissues involved in glucose homeostasis are scarce and the transcriptomic regulation of genes involved in BCAA catabolism is partially unknown. This study aimed to identify differences in circulating and skeletal muscle BCAA levels in response to an OGTT in individuals with normal glucose tolerance (NGT) or type 2 diabetes. Additionally, transcription factors involved in the regulation of the BCAA gene set were identified. Methods Plasma and vastus lateralis muscle biopsies were obtained from individuals with NGT or type 2 diabetes before and after an OGTT. Plasma and quadriceps muscles were harvested from skeletal muscle-specific Ppargc1a knockout and transgenic mice. BCAA-related metabolites and genes were assessed by LC-MS/MS and quantitative RT-PCR, respectively. Small interfering RNA and adenovirus-mediated overexpression techniques were used in primary human skeletal muscle cells to study the role of PPARGC1A and ESRRA in the expression of the BCAA gene set. Radiolabelled leucine was used to analyse the impact of oestrogen-related receptor α (ERRα) knockdown on leucine oxidation. Results Impairments in BCAA catabolism in people with type 2 diabetes under fasting conditions were exacerbated after a glucose load. Branched-chain keto acids were reduced 37–56% after an OGTT in the NGT group, whereas no changes were detected in individuals with type 2 diabetes. These changes were concomitant with a stronger correlation with glucose homeostasis biomarkers and downregulated expression of branched-chain amino acid transaminase 2, branched-chain keto acid dehydrogenase complex subunits and 69% of downstream BCAA-related genes in skeletal muscle. In primary human myotubes overexpressing peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α, encoded by PPARGC1A), 61% of the analysed BCAA genes were upregulated, while 67% were downregulated in the quadriceps of skeletal muscle-specific Ppargc1a knockout mice. ESRRA (encoding ERRα) silencing completely abrogated the PGC-1α-induced upregulation of BCAA-related genes in primary human myotubes. Conclusions/interpretation Metabolic inflexibility in type 2 diabetes impacts BCAA homeostasis and attenuates the decrease in circulating and skeletal muscle BCAA-related metabolites after a glucose challenge. Transcriptional regulation of BCAA genes in primary human myotubes via PGC-1α is ERRα-dependent. Graphical abstract

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241 Skeletal Muscle Mitochondrial Capacities Are Impacted by Breed and Temperament in Young Angus and Brahman Steers

Journal of Animal Science ◽

10.1093/jas/skab235.231 ◽

2021 ◽

Vol 99 (Supplement_3) ◽

pp. 127-127

Author(s):

Chloey P Guy ◽

Lauren T Wesolowski ◽

Audrey L Earnhardt ◽

Dustin Law ◽

Don A Neuendorff ◽

...

Keyword(s):

Skeletal Muscle ◽

Fixed Effects ◽

Linear Models ◽

Citrate Synthase ◽

Volume Density ◽

Skeletal Muscle Mitochondria ◽

Mitochondrial Volume ◽

Mitochondrial Volume Density ◽

Brahman Steers ◽

The Impact

Abstract Temperament impacts skeletal muscle mitochondria in Brahman heifers, but this has not been investigated in steers or between cattle breeds. We hypothesized mitochondrial measures would be greater in Angus than Brahman, temperamental than calm steers, and the trapezius (TRAP) than the longissimus thoracis (LT) muscle. Samples from calm (n = 13 per breed), intermediate (n = 12 per breed), and temperamental (n=13 per breed) Angus and Brahman steers (mean±SD 10.0±0.8 mo) were evaluated for mitochondrial enzyme activities via colorimetry. Calm and temperamental LT samples were evaluated for oxidative phosphorylation (P) and electron transfer (E) capacities by high-resolution respirometry. Data were analyzed using linear models with fixed effects of breed, muscle, temperament, and all interactions. Brahman tended to have greater mitochondrial volume density (citrate synthase activity; CS) than Angus (P = 0.08), while intrinsic (relative to CS) mitochondrial function (cytochrome c oxidase activity) was greater in Angus than Brahman (P = 0.001) and greater in TRAP than LT (P = 0.008). Angus exhibited greater integrative (per mg tissue) and intrinsic P with complex I (PCI), P with complexes I+II (PCI+II), maximum noncoupled E, and E with complex II (ECII; P ≤ 0.04) and tended to have greater intrinsic leak (P = 0.1) than Brahman. Contribution of PCI to total E was greater in Angus than Brahman (P = 0.01), while contribution of ECII to total E was greater in Brahman than Angus (P = 0.05). A trend for the interaction of breed and temperament (P = 0.07) indicated calm Angus had the greatest intrinsic ECII (P ≤ 0.03) while intrinsic ECII was similar between temperamental Angus and calm and temperamental Brahman. Integrative PCI+II and ECII, and the contribution of PCI and PCI+II to overall E tended to be greater in temperamental than calm steers (P ≤ 0.09), while intrinsic ECII tended to be greater in calm than temperamental steers (P = 0.07). The impact of these mitochondrial differences on meat quality measures remains to be determined.

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AMP-Activated Protein Kinase as a Key Trigger for the Disuse-Induced Skeletal Muscle Remodeling

International Journal of Molecular Sciences ◽

10.3390/ijms19113558 ◽

2018 ◽

Vol 19 (11) ◽

pp. 3558 ◽

Cited By ~ 13

Author(s):

Natalia Vilchinskaya ◽

Igor Krivoi ◽

Boris Shenkman

Keyword(s):

Skeletal Muscle ◽

Protein Kinase ◽

Histone Deacetylases ◽

Molecular Mechanisms ◽

Weight Bearing ◽

Mammalian Target Of Rapamycin ◽

Adenosine Monophosphate ◽

Chain Gene ◽

Mtorc1 Signaling ◽

The Impact

Molecular mechanisms that trigger disuse-induced postural muscle atrophy as well as myosin phenotype transformations are poorly studied. This review will summarize the impact of 5′ adenosine monophosphate -activated protein kinase (AMPK) activity on mammalian target of rapamycin complex 1 (mTORC1)-signaling, nuclear-cytoplasmic traffic of class IIa histone deacetylases (HDAC), and myosin heavy chain gene expression in mammalian postural muscles (mainly, soleus muscle) under disuse conditions, i.e., withdrawal of weight-bearing from ankle extensors. Based on the current literature and the authors’ own experimental data, the present review points out that AMPK plays a key role in the regulation of signaling pathways that determine metabolic, structural, and functional alternations in skeletal muscle fibers under disuse.

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TWIST1 and TWIST2 regulate glycogen storage and inflammatory genes in skeletal muscle

Journal of Endocrinology ◽

10.1530/joe-14-0474 ◽

2015 ◽

Vol 224 (3) ◽

pp. 303-313 ◽

Cited By ~ 7

Author(s):

Jonathan M Mudry ◽

Julie Massart ◽

Ferenc L M Szekeres ◽

Anna Krook

Keyword(s):

Skeletal Muscle ◽

Metabolic Diseases ◽

Glycogen Synthesis ◽

C2c12 Cells ◽

Acid Oxidation ◽

Diabetic Patients ◽

Mrna Levels ◽

Intact Mouse ◽

Mouse Muscle ◽

The Impact

TWIST proteins are important for development of embryonic skeletal muscle and play a role in the metabolism of tumor and white adipose tissue. The impact of TWIST on metabolism in skeletal muscle is incompletely studied. Our aim was to assess the impact of TWIST1 and TWIST2 overexpression on glucose and lipid metabolism. In intact mouse muscle, overexpression of Twist reduced total glycogen content without altering glucose uptake. Expression of TWIST1 or TWIST2 reducedPdk4mRNA, while increasing mRNA levels ofIl6,Tnfα, andIl1β. Phosphorylation of AKT was increased and protein abundance of acetyl CoA carboxylase (ACC) was decreased in skeletal muscle overexpressing TWIST1 or TWIST2. Glycogen synthesis and fatty acid oxidation remained stable in C2C12 cells overexpressing TWIST1 or TWIST2. Finally, skeletal muscle mRNA levels remain unaltered inob/obmice, type 2 diabetic patients, or in healthy subjects before and after 3 months of exercise training. Collectively, our results indicate that TWIST1 and TWIST2 are expressed in skeletal muscle. Overexpression of these proteins impacts proteins in metabolic pathways and mRNA level of cytokines. However, skeletal muscle levels of TWIST transcripts are unaltered in metabolic diseases.

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Type 2 diabetes mellitus in the Goto-Kakizaki rat impairs microvascular function and contributes to premature skeletal muscle fatigue

Journal of Applied Physiology ◽

10.1152/japplphysiol.00751.2018 ◽

2019 ◽

Vol 126 (3) ◽

pp. 626-637 ◽

Cited By ~ 6

Author(s):

Jefferson C. Frisbee ◽

Matthew T. Lewis ◽

Jonathan D. Kasper ◽

Paul D. Chantler ◽

Robert W. Wiseman

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Skeletal Muscle ◽

Type 2 Diabetes Mellitus ◽

Structure Function ◽

Vascular Structure ◽

Gk Rats ◽

The Impact

Despite extensive investigation into the impact of metabolic disease on vascular function and, by extension, tissue perfusion and organ function, interpreting results for specific risk factors can be complicated by the additional risks present in most models. To specifically determine the impact of type 2 diabetes without obesity on skeletal muscle microvascular structure/function and on active hyperemia with elevated metabolic demand, we used 17-wk-old Goto-Kakizaki (GK) rats to study microvascular function at multiple levels of resolution. Gracilis muscle arterioles demonstrated blunted dilation to acetylcholine (both ex vivo proximal and in situ distal arterioles) and elevated shear (distal arterioles only). All other alterations to reactivity appeared to reflect compromised endothelial function associated with increased thromboxane (Tx)A2 production and oxidant stress/inflammation rather than alterations to vascular smooth muscle function. Structural changes to the microcirculation of GK rats were confined to reduced microvessel density of ~12%, with no evidence for altered vascular wall mechanics. Active hyperemia with either field stimulation of in situ cremaster muscle or electrical stimulation via the sciatic nerve for in situ gastrocnemius muscle was blunted in GK rats, primarily because of blunted functional dilation of skeletal muscle arterioles. The blunted active hyperemia was associated with impaired oxygen uptake (V̇o2) across the muscle and accelerated muscle fatigue. Acute interventions to reduce oxidant stress (TEMPOL) and TxA2 action (SQ-29548) or production (dazmegrel) improved muscle perfusion, V̇o2, and muscle performance. These results suggest that type 2 diabetes mellitus in GK rats impairs skeletal muscle arteriolar function apparently early in the progression of the disease and potentially via an increased reactive oxygen species/inflammation-induced TxA2 production/action on network function as a major contributing mechanism. NEW & NOTEWORTHY The impact of type 2 diabetes mellitus on vascular structure/function remains an area lacking clarity. Using diabetic Goto-Kakizaki rats before the development of other risk factors, we determined alterations to vascular structure/function and skeletal muscle active hyperemia. Type 2 diabetes mellitus reduced arteriolar endothelium-dependent dilation associated with increased thromboxane A2 generation. Although modest microvascular rarefaction was evident, there were no other alterations to vascular structure/function. Skeletal muscle active hyperemia was blunted, although it improved after antioxidant or anti-thromboxane A2 treatment.

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Inhibiting myosin-ATPase reveals a dynamic range of mitochondrial respiratory control in skeletal muscle

Biochemical Journal ◽

10.1042/bj20110366 ◽

2011 ◽

Vol 437 (2) ◽

pp. 215-222 ◽

Cited By ~ 93

Author(s):

Christopher G. R. Perry ◽

Daniel A. Kane ◽

Chien-Te Lin ◽

Rachel Kozy ◽

Brook L. Cathey ◽

...

Keyword(s):

Skeletal Muscle ◽

Dynamic Range ◽

Energy Charge ◽

Respiratory Control ◽

Basic Research ◽

Dependent Manner ◽

Atpase Inhibitor ◽

Wide Range ◽

The Impact

Assessment of mitochondrial ADP-stimulated respiratory kinetics in PmFBs (permeabilized fibre bundles) is increasingly used in clinical diagnostic and basic research settings. However, estimates of the Km for ADP vary considerably (~20–300 μM) and tend to overestimate respiration at rest. Noting that PmFBs spontaneously contract during respiration experiments, we systematically determined the impact of contraction, temperature and oxygenation on ADP-stimulated respiratory kinetics. BLEB (blebbistatin), a myosin II ATPase inhibitor, blocked contraction under all conditions and yielded high Km values for ADP of >~250 and ~80 μM in red and white rat PmFBs respectively. In the absence of BLEB, PmFBs contracted and the Km for ADP decreased ~2–10-fold in a temperature-dependent manner. PmFBs were sensitive to hyperoxia (increased Km) in the absence of BLEB (contracted) at 30 °C but not 37 °C. In PmFBs from humans, contraction elicited high sensitivity to ADP (Km<100 μM), whereas blocking contraction (+BLEB) and including a phosphocreatine/creatine ratio of 2:1 to mimic the resting energetic state yielded a Km for ADP of ~1560 μM, consistent with estimates of in vivo resting respiratory rates of <1% maximum. These results demonstrate that the sensitivity of muscle to ADP varies over a wide range in relation to contractile state and cellular energy charge, providing evidence that enzymatic coupling of energy transfer within skeletal muscle becomes more efficient in the working state.

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