Dystrophin deficiency disrupts muscle clock expression and mitochondrial quality control in mdx mice.

Impaired oxidative capacity and mitochondrial function contribute to the dystrophic pathology in muscles of patients with Duchenne muscular dystrophy (DMD) and in relevant mouse models of the disease. Emerging evidence suggests an association between disrupted core clock expression and mitochondrial quality control, but this has not been established in muscles lacking dystrophin. We examined the diurnal regulation of muscle core clock and mitochondrial quality control expression in dystrophin-deficient C57BL/10ScSn-Dmdmdx (mdx) mice, an established model of DMD. Male C57BL/10 (BL/10; n = 18) and mdx mice (n = 18) were examined every 4 h beginning at the dark cycle. Throughout the entire light-dark cycle, extensor digitorum longus (EDL) muscles from mdx mice had decreased core clock mRNA expression (Arntl, Cry1, Cry2, Nr1d2; P < 0.05) and disrupted mitochondrial quality control mRNA expression related to biogenesis (decreased; Ppargc1a, Esrra; P < 0.05), fission (increased; Dnm1l; P < 0.01), fusion (decreased; Opa1, Mfn1; P < 0.05), and autophagy/mitophagy (decreased: Bnip3; P < 0.05; increased: Becn1; P < 0.05). Cosinor analysis revealed a decrease in the rhythmicity parameters mesor and amplitude for Arntl, Cry1, Cry2, Per2, and Nr1d1 (P < 0.001) in mdx mice. Diurnal oscillations in Esrra, Sirt1, Map1lc3b, and Sqstm1 were absent in mdx mice, along with decreased mesor and amplitude of Ppargc1a mRNA expression (P < 0.01). The expression of proteins involved in mitochondrial biogenesis (decreased: PPARGC1A, P < 0.05) and autophagy/mitophagy (increased: MAP1LC3BII, SQSTM1, BNIP3; P < 0.05) were also dysregulated in tibialis anterior muscles of mdx mice. These findings suggest that dystrophin deficiency in mdx mice impairs the regulation of the core clock and mitochondrial quality control, with relevance to DMD and related disorders.

Functional electrical stimulation in-bed cycle ergometry in mechanically ventilated patients: a multicentre randomised controlled trial.

PURPOSE: To investigate the effect of functional electrical stimulation-assisted cycle ergometry (FES-cycling) on muscle strength, cognitive impairment and related outcomes. METHODS: Mechanically ventilated patients aged ≥18 years with sepsis or systemic inflammatory response syndrome were randomised to either 60 min of FES-cycling >5 days/week while in the intensive care unit (ICU) plus usual care rehabilitation versus usual care rehabilitation alone, with evaluation of two primary outcomes: (1) muscle strength at hospital discharge and (2) cognitive impairment at 6-month follow-up. RESULTS: We enrolled 162 participants, across four study sites experienced in ICU rehabilitation in Australia and the USA, to FES-cycling (n=80; mean age±SD 59±15) versus control (n=82; 56±14). Intervention participants received a median (IQR) of 5 (3-9) FES-cycling sessions with duration of 56 (34-63) min/day plus 15 (10-23) min/day of usual care rehabilitation. The control group received 15 (8-15) min/day of usual care rehabilitation. In the intervention versus control group, there was no significant differences for muscle strength at hospital discharge (mean difference (95% CI) 3.3 (-5.0 to 12.1) Nm), prevalence of cognitive impairment at 6 months (OR 1.1 (95% CI 0.30 to 3.8)) or secondary outcomes measured in-hospital and at 6 and 12 months follow-up. CONCLUSION: In this randomised controlled trial, undertaken at four centres with established rehabilitation programmes, the addition of FES-cycling to usual care rehabilitation did not substantially increase muscle strength at hospital discharge. At 6 months, the incidence of cognitive impairment was almost identical between groups, but potential benefit or harm of the intervention on cognition cannot be excluded due to imprecision of the estimated effect. TRIAL REGISTRATION NUMBER: ACTRN 12612000528853, NCT02214823.

Protein Type, Protein Dose, and Age Modulate Dietary Protein Digestion and Phenylalanine Absorption Kinetics and Plasma Phenylalanine Availability in Humans.

BACKGROUND: Dietary protein ingestion stimulates muscle protein synthesis by providing amino acids to the muscle. The magnitude and duration of the postprandial increase in muscle protein synthesis rates are largely determined by dietary protein digestion and amino acid absorption kinetics. OBJECTIVE: We assessed the impact of protein type, protein dose, and age on dietary protein digestion and amino acid absorption kinetics in vivo in humans. METHODS: We included data from 18 randomized controlled trials with a total of 602 participants [age: 53 ± 23 y; BMI (kg/m2): 24.8 ± 3.3] who consumed various quantities of intrinsically l-[1-13C]-phenylalanine-labeled whey (n = 137), casein (n = 393), or milk (n = 72) protein and received intravenous infusions of l-[ring-2H5]-phenylalanine, which allowed us to assess protein digestion and phenylalanine absorption kinetics and the postprandial release of dietary protein-derived phenylalanine into the circulation. The effect of aging on these processes was assessed in a subset of 82 young (aged 22 ± 3 y) and 83 older (aged 71 ± 5 y) individuals. RESULTS: A total of 50% ± 14% of dietary protein-derived phenylalanine appeared in the circulation over a 5-h postprandial period. Casein ingestion resulted in a smaller (45% ± 11%), whey protein ingestion in an intermediate (57% ± 10%), and milk protein ingestion in a greater (65% ± 13%) fraction of dietary protein-derived phenylalanine appearing in the circulation (P < 0.001). The postprandial availability of dietary protein-derived phenylalanine in the circulation increased with the ingestion of greater protein doses (P < 0.05). Protein digestion and phenylalanine absorption kinetics were attenuated in older when compared with young individuals, with 45% ± 10% vs. 51% ± 14% of dietary protein-derived phenylalanine appearing in the circulation, respectively (P = 0.001). CONCLUSIONS: Protein type, protein dose, and age modulate dietary protein digestion and amino acid absorption kinetics and subsequent postprandial plasma amino acid availability in vivo in humans. These trials were registered at clinicaltrials.gov as NCT00557388, NCT00936039, NCT00991523, NCT01317511, NCT01473576, NCT01576848, NCT01578590, NCT01615276, NCT01680146, NCT01820975, NCT01986842, and NCT02596542, and at http://www.trialregister.nl as NTR3638, NTR3885, NTR4060, NTR4429, and NTR4492.

BGP-15 Improves Aspects of the Dystrophic Pathology in mdx and dko Mice with Differing Efficacies in Heart and Skeletal Muscle.

Duchenne muscular dystrophy is a severe and progressive striated muscle wasting disorder that leads to premature death from respiratory and/or cardiac failure. We have previously shown that treatment of young dystrophic mdx and dystrophin/utrophin null (dko) mice with BGP-15, a coinducer of heat shock protein 72, ameliorated the dystrophic pathology. We therefore tested the hypothesis that later-stage BGP-15 treatment would similarly benefit older mdx and dko mice when the dystrophic pathology was already well established. Later stage treatment of mdx or dko mice with BGP-15 did not improve maximal force of tibialis anterior (TA) muscles (in situ) or diaphragm muscle strips (in vitro). However, collagen deposition (fibrosis) was reduced in TA muscles of BGP-15-treated dko mice but unchanged in TA muscles of treated mdx mice and diaphragm of treated mdx and dko mice. We also examined whether BGP-15 treatment could ameliorate aspects of the cardiac pathology, and in young dko mice it reduced collagen deposition and improved both membrane integrity and systolic function. These results confirm BGP-15's ability to improve aspects of the dystrophic pathology but with differing efficacies in heart and skeletal muscles at different stages of the disease progression. These findings support a role for BGP-15 among a suite of pharmacological therapies for Duchenne muscular dystrophy and related disorders.

Glycine metabolism in skeletal muscle: implications for metabolic homeostasis.

PURPOSE OF REVIEW: The review summarizes the recent literature on the role of glycine in skeletal muscle during times of stress. RECENT FINDINGS: Supplemental glycine protects muscle mass and function under pathological conditions. In addition, mitochondrial dysfunction in skeletal muscle leads to increased cellular serine and glycine production and activation of NADPH-generating pathways and glutathione metabolism. These studies highlight how glycine availability modulates cellular homeostasis and redox status. SUMMARY: Recent studies demonstrate that supplemental glycine effectively protects muscles in a variety of wasting models, including cancer cachexia, sepsis, and reduced caloric intake. The underlying mechanisms responsible for the effects of glycine remain unclear but likely involve receptor-mediated responses and modulation of intracellular metabolism. Future research to understand these mechanisms will provide insight into glycine's therapeutic potential. Our view is that glycine holds considerable promise for improving health by protecting muscles during different wasting conditions.

Glycine restores the anabolic response to leucine in a mouse model of acute inflammation.

Amino acids, especially leucine, potently stimulate protein synthesis and reduce protein breakdown in healthy skeletal muscle and as a result have received considerable attention as potential treatments for muscle wasting. However, the normal anabolic response to amino acids is impaired during muscle-wasting conditions. Although the exact mechanisms of this anabolic resistance are unclear, inflammation and ROS are believed to play a central role. The nonessential amino acid glycine has anti-inflammatory and antioxidant properties and preserves muscle mass in calorie-restricted and tumor-bearing mice. We hypothesized that glycine would restore the normal muscle anabolic response to amino acids under inflammatory conditions. Relative rates of basal and leucine-stimulated protein synthesis were measured using SUnSET methodology 4 h after an injection of 1 mg/kg lipopolysaccharide (LPS). Whereas leucine failed to stimulate muscle protein synthesis in LPS-treated mice pretreated with l-alanine (isonitrogenous control), leucine robustly stimulated protein synthesis (+51%) in mice pretreated with 1 g/kg glycine. The improvement in leucine-stimulated protein synthesis was accompanied by a higher phosphorylation status of mTOR, S6, and 4E-BP1 compared with l-alanine-treated controls. Despite its known anti-inflammatory action in inflammatory cells, glycine did not alter the skeletal muscle inflammatory response to LPS in vivo or in vitro but markedly reduced DHE staining intensity, a marker of oxidative stress, in muscle cross-sections and attenuated LPS-induced wasting in C2C12 myotubes. Our observations in male C57BL/6 mice suggest that glycine may represent a promising nutritional intervention for the attenuation of skeletal muscle wasting.

Amino acid sensing and activation of mechanistic target of rapamycin complex 1: implications for skeletal muscle.

PURPOSE OF REVIEW: This article evaluates recent studies on the mechanisms involved in sensing changes in amino acid availability and activation of the mechanistic target of rapamycin complex 1 (mTORC1). RECENT FINDINGS: mTORC1 is sensitive to changes in amino acid availability and a well known regulator of protein turnover. The mechanisms of amino acid sensing and mTORC1 signaling are emerging with multiple potential sensors (e.g., solute carrier family 38, member 9, lysosomal protein transmembrane 4 beta/solute carrier family 7, member 5-solute carrier family 3, member 2) and signal transducers (e.g., Sestrins, ADP-ribosylation factor 1, and microspherule protein 1) identified. Studies in various cell lines have unveiled the importance of the lysosome in amino acid sensing and signal transmission. SUMMARY: Recent discoveries in amino acid sensing highlight a complex scenario, whereby mTORC1 is not merely sensitive to some amino acids and not others, but where specific amino acids are sensed by specific pathways under specific conditions. The physiological purpose of such an arrangement remains to be unraveled, but it would allow mTORC1 to precisely regulate growth during different metabolic conditions. Understanding the mechanisms responsible for sensing amino acid availability and regulating mTORC1 activity is an important prerequisite for the development of nutritional strategies to combat skeletal muscle wasting disorders.

Citrulline does not prevent skeletal muscle wasting or weakness in limb-casted mice.

BACKGROUND: Increasing arginine (Arg) availability reduces atrophy in cultured skeletal muscle cells. Supplementation with its metabolic precursor citrulline (Cit) is more effective at improving skeletal muscle Arg concentrations. OBJECTIVE: We tested the hypothesis that Cit supplementation would attenuate skeletal muscle atrophy and loss of function during hindlimb immobilization in mice. METHODS: Male C57BL/6JArc mice underwent 14 d of unilateral hindlimb immobilization/plaster casting and were supplemented with ~0.81 g Cit · kg⁻¹ · d⁻¹ (CIT group) or Ala (ALA group) mixed into their food. The uncasted contralateral limb (internal control) and an uncasted group (CON) served as controls. Muscle atrophy was evaluated with mass, fiber area, and in situ muscle function. RESULTS: Tibialis anterior (TA) muscle mass [ALA: 37.6 ± 0.92 mg; CIT: 38.3 ± 1.25 mg] and peak tetanic force (ALA: 1150 ± 38.5 mN; CIT: 1150 ± 52.0 mN) were lower (P < 0.001) in the ALA (53.9 ± 0.42 mg) and CIT (1760 ± 28.5 mN) groups than in the CON group. No difference was found between ALA and CIT groups for TA mass, fiber area, or peak force. The mRNA expression of the nitric oxide synthase 2, inducible (Nos2; ~15-fold) and B-cell chronic lymphoid leukemia/lymphoma 2/adenovirus E1B 19 kDa interacting protein 3 (Bnip3; ~17-fold) genes and the ratio of microtubule-associated protein light chain 3BII to 3BI (LC3BII:LC3BI) (50.5% ± 17.7%) were higher (P < 0.05) in the ALA group than in the CON group, suggesting increased autophagy. In the CIT group, Bnip3 mRNA was lower (-70%; P < 0.05) and Nos2 mRNA tended to be lower (-45%; P = 0.05) than in the ALA group, whereas LC3BII:LC3BI was not different from the CON group. CONCLUSIONS: Cit treatment of male mice did not affect therapeutically relevant outcome measures such as skeletal muscle mass and peak muscle force after 14 d of hindlimb immobilization.

A new two-tier strength assessment approach to the diagnosis of weakness in intensive care: an observational study.

INTRODUCTION: Intensive care unit-acquired weakness (ICU-AW) is a significant problem. There is currently widespread variability in the methods used for manual muscle testing and handgrip dynamometry (HGD) to diagnose ICU-AW. This study was conducted in two parts. The aims of this study were: to determine the inter-rater reliability and agreement of manual muscle strength testing using both isometric and through-range techniques using the Medical Research Council sum score and a new four-point scale, and to examine the validity of HGD and determine a cutoff score for the diagnosis of ICU-AW for the new four-point scale. METHODS: Part one involved evaluation of muscle strength by two physical therapists in 29 patients ventilated >48 hours. Manual strength testing was performed by both physical therapists using two techniques: isometric and through range; and two scoring systems: traditional six-point Medical Research Council scale and a new collapsed four-point scale. Part two involved assessment of handgrip strength conducted on 60 patients. A cutoff score for ICU-AW was identified for the new four-point scoring system. RESULTS: The incidence of ICU-AW was 42% (n = 25/60) in this study (based on HGD). In part one the highest reliability and agreement was observed for the isometric technique using the four-point scale (intraclass correlation coefficient = 0.90: kappa = 0.72 respectively). Differences existed between isometric and through-range scores (mean difference = 1.76 points, P = 0.005). In part two, HGD had a sensitivity of 0.88 and specificity of 0.80 for diagnosing ICU-AW. A cutoff score of 24 out of 36 points was identified for the four-point scale. CONCLUSIONS: The isometric technique is recommended with reporting on a collapsed four-point scale. Because HGD is easy to perform and sensitive, we recommend a new two-tier approach to diagnosing ICU-AW that first tests handgrip strength with follow-up strength assessment using the isometric technique for muscle strength testing if handgrip strength falls below cutoff scores. Whilst our results for the four-point scale are encouraging, further research is required to confirm the findings of this study and determine the validity of the four-point scoring system and cutoff score developed of less than 24 out of 36 before recommending adoption into clinical practice.

Arginine protects muscle cells from wasting in vitro in an mTORC1-dependent and NO-independent manner.

Amino acids are potent regulators of muscle protein synthesis and breakdown and have received considerable attention for the treatment of muscle wasting conditions. Arginine is critically involved in numerous physiological functions including providing substrate for the production of creatine, urea and nitric oxide (NO) and in the synthesis of new proteins. However, little is known about the direct effects of arginine on skeletal muscle protein synthesis during catabolic conditions. The aims of this study were to determine whether exogenous arginine could protect skeletal muscle cells from wasting directly and whether this effect was dependent on production of NO and/or activation of the rapamycin-sensitive mechanistic target of rapamycin complex 1 (mTORC1) signalling pathway. To explore these aims, we deprived mature C2C12 myotubes from nutrients and growth factors by incubating them in HEPES buffered saline with arginine or equimolar concentrations of alanine (control). Our results show that arginine: increased the ratio of phosphorylated to total mTOR (146 %), S6 (40 %) and 4EBP1 (69 %); increased protein synthesis (69 %) during the first hour of treatment; and increased myotube diameter by ~15 %. Experiments using the NO synthase inhibitor L-NG-Nitroarginine Methyl Ester showed a NO-independent protection from muscle wasting. On the other hand, the mTORC1 inhibitor rapamycin prevented increases in phosphorylated S6, protein synthesis and myotube diameter. The activation of mTORC1 and protein synthesis by arginine was not associated with changes in the phosphorylation status of Akt, but rather increased the expression of the amino acid-sensitive type III PI3-kinase Vps34 signalling protein. These data support a direct role for arginine in the regulation of mTORC1 in skeletal muscle.

Plasma beta-hydroxy-beta-methylbutyrate availability after enteral administration during critical illness after trauma: An exploratory study.

BACKGROUND: During critical illness skeletal muscle wasting occurs rapidly. Although beta-hydroxy-beta-methylbutyrate (HMB) is a potential treatment to attenuate this process, the plasma appearance and muscle concentration is uncertain. METHODS: This was an exploratory study nested within a blinded, parallel group, randomized clinical trial in which critically ill patients after trauma received enteral HMB (3 g daily) or placebo. Plasma samples were collected at 0, 60, and 180 min after study supplement administration on day 1. Needle biopsies of the vastus lateralis muscle were collected (baseline and day 7 of the HMB treatment intervention period). An external standard curve was used to calculate HMB concentrations in plasma and muscle. RESULTS: Data were available for 16 participants (male n = 12 (75%), median [interquartile range] age 50 [29-58] years) who received placebo and 18 participants (male n = 14 (78%), age 49 [34-55] years) who received HMB. Plasma HMB concentrations were similar at baseline but increased after HMB (T = 60 min: placebo 0.60 [0.44-1.31] µM; intervention 51.65 [22.76-64.72] µM). Paired muscle biopsies were collected from 11 participants (placebo n = 7, HMB n = 4). Muscle HMB concentrations were similar at baseline between groups (2.35 [2.17-2.95]; 2.07 [1.78-2.31] µM). For participants in the intervention group who had the repeat biopsy within 4 h of HMB administration, concentrations were greater (7.2 and 12.3 µM) than those who had the repeat biopsy >4 h after HMB (2.7 and 2.1 µM). CONCLUSION: In this exploratory study, enteral HMB administration increased plasma HMB availability. The small sample size limits interpretation of the muscle HMB findings.

Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia.

Mitochondrial dysfunction and low nicotinamide adenine dinucleotide (NAD+) levels are hallmarks of skeletal muscle ageing and sarcopenia1-3, but it is unclear whether these defects result from local changes or can be mediated by systemic or dietary cues. Here we report a functional link between circulating levels of the natural alkaloid trigonelline, which is structurally related to nicotinic acid4, NAD+ levels and muscle health in multiple species. In humans, serum trigonelline levels are reduced with sarcopenia and correlate positively with muscle strength and mitochondrial oxidative phosphorylation in skeletal muscle. Using naturally occurring and isotopically labelled trigonelline, we demonstrate that trigonelline incorporates into the NAD+ pool and increases NAD+ levels in Caenorhabditis elegans, mice and primary myotubes from healthy individuals and individuals with sarcopenia. Mechanistically, trigonelline does not activate GPR109A but is metabolized via the nicotinate phosphoribosyltransferase/Preiss-Handler pathway5,6 across models. In C. elegans, trigonelline improves mitochondrial respiration and biogenesis, reduces age-related muscle wasting and increases lifespan and mobility through an NAD+-dependent mechanism requiring sirtuin. Dietary trigonelline supplementation in male mice enhances muscle strength and prevents fatigue during ageing. Collectively, we identify nutritional supplementation of trigonelline as an NAD+-boosting strategy with therapeutic potential for age-associated muscle decline.

Electrical muscle stimulation in the intensive care setting: a systematic review.

CONTEXT: The role of electrical muscle stimulation in intensive care has not previously been systematically reviewed. OBJECTIVES: To identify, evaluate, and synthesize the evidence examining the effectiveness and the safety of electrical muscle stimulation in the intensive care, and the optimal intervention variables. DATA SOURCES: A systematic review of articles using eight electronic databases (Cumulative Index to Nursing and Allied Health Literature, Cochrane Library, Excerpta Medica Database, Expanded Academic ASAP, MEDLINE, Physiotherapy Evidence Database, PubMed, and Scopus) personal files were searched, and cross-referencing was undertaken. ELIGIBILITY CRITERIA: Quantitative studies published in English, assessing electrical muscle stimulation in intensive care, were included. DATA EXTRACTION AND DATA SYNTHESIS: One reviewer extracted data using a standardized form, which were cross-checked by a second reviewer. Quality appraisal was undertaken by two independent reviewers using the Physiotherapy Evidence Database and Newcastle-Ottawa scales, and the National Health and Medical Research Council Hierarchy of Evidence Scale. Preferred Reporting Items for Systematic Reviews guidelines were followed. RESULTS: Nine studies on six individual patient groups of 136 participants were included. Eight were randomized controlled trials, with four studies reporting on the same cohort of participants. Electrical muscle stimulation appears to preserve muscle mass and strength in long-stay participants and in those with less acuity. No such benefits were observed when commenced prior to 7 days or in patients with high acuity. One adverse event was reported. Optimal training variables and safety of the intervention require further investigation. CONCLUSIONS: Electrical muscle stimulation is a promising intervention; however, there is conflicting evidence for its effectiveness when administered acutely. Outcomes measured are heterogeneous with small sample sizes.

Normal rates of whole-body fat oxidation and gluconeogenesis after overnight fasting and moderate-intensity exercise in patients with medium-chain acyl-CoA dehydrogenase deficiency.

BACKGROUND: Impairments in gluconeogenesis have been implicated in the pathophysiology of fasting hypoglycemia in medium-chain acyl-CoA dehydrogenase deficiency. However, whole body glucose and fat metabolism have never been studied in vivo. METHODS: Stable isotope methodology was applied to compare fat and glucose metabolism between four adult patients with MCADD and four matched controls both at rest and during 1.5 h of moderate-intensity exercise. Additionally, intramyocellular lipid and glycogen content and intramyocellular acylcarnitines were assessed in muscle biopsies collected prior to and immediately after cessation of exercise. RESULTS: At rest, plasma FFA turnover was significantly higher in patients with MCADD, whereas the plasma FFA concentrations did not differ between patients and controls. Blood glucose kinetics did not differ between groups both at rest and during exercise. Palmitate and FFA turnover, total fat and carbohydrate oxidation rates, the use of muscle glycogen and muscle derived triglycerides during exercise did not differ between patients and controls. Plasma FFA oxidation rates were significantly lower in patients at the latter stages of exercise. Free carnitine levels in muscle were lower in patients, whereas no differences were detected in muscle acetylcarnitine levels. CONCLUSIONS: Whole-body or skeletal muscle glucose and fat metabolism were not impaired in adult patients with MCADD. This implies that MCADD is not rate limiting for energy production under the conditions studied. In addition, patients with MCADD have a higher FFA turnover rate after overnight fasting, which may stimulate ectopic lipid deposition and, as such, make them more susceptible for developing insulin resistance.

Age-Related Changes in Skeletal Muscle Iron Homeostasis.

Sarcopenia is an age-related condition of slow, progressive loss of muscle mass and strength, which contributes to frailty, increased risk of hospitalization and mortality, and increased health care costs. The incidence of sarcopenia is predicted to increase to >200 million affected older adults worldwide over the next 40 years, highlighting the urgency for understanding biological mechanisms and developing effective interventions. An understanding of the mechanisms underlying sarcopenia remains incomplete. Iron in the muscle is important for various metabolic functions, including oxygen supply and electron transfer during energy production, yet these same chemical properties of iron may be deleterious to the muscle when either in excess or when biochemically unshackled (eg, in ferroptosis), it can promote oxidative stress and induce inflammation. This review outlines the mechanisms leading to iron overload in muscle with aging and evaluates the evidence for the iron overload hypothesis of sarcopenia. Based on current evidence, studies are needed to (a) determine the mechanisms leading to iron overload in skeletal muscle during aging; and (b) investigate whether skeletal muscles are functionally deficient in iron during aging leading to impairments in oxidative metabolism.

Beta-hydroxy-beta-methylbutyrate supplementation and functional outcomes in multitrauma patients: A pilot randomized controlled trial.

BACKGROUND: Beta-hydroxy-beta-methylbutyrate (HMB) is a nutrition supplement that may attenuate muscle wasting from critical illness. This trial aimed to determine feasibility of administering a blinded nutrition supplement in the intensive care unit (ICU) and continuing it after ICU discharge. METHODS: Single-center, parallel-group, blinded, placebo-controlled, randomized feasibility trial. After traumatic injury necessitating admission to ICU, participants were randomized to receive an enteral study supplement of 3 g of HMB (intervention) or placebo daily for 28 days or until hospital discharge. Primary outcome was feasibility of administering the study supplement, quantified as protocol adherence. Secondary outcomes included change in quadriceps muscle thickness, measured weekly until day 28 or hospital discharge by using ultrasound and analyzed by using a linear mixed model. RESULTS: Fifty randomized participants (intervention, n = 26; placebo, n = 24) showed comparable baseline characteristics. Participants received 862 (84.3%) of the 1022 prescribed supplements during hospitalization with 543 (62.8%) delivered via an enteral feeding tube. The median (IQR) number of study supplements successfully administered per participant was 19.5 (13.0-24.0) in the intervention group and 16.5 (8.5-23.5) in the placebo group. Marked loss of quadriceps muscle thickness occurred in both groups, with the point estimate favoring attenuated muscle loss with the intervention, albeit with wide CIs (mean intervention difference after 28 days, 0.26 cm [95% CI, -0.13 to 0.64]). CONCLUSION: A blinded, placebo-controlled, randomized clinical trial of daily enteral HMB supplementation for up to 28 days in hospital is feasible. Any effect of HMB supplementation to attenuate muscle wasting after traumatic injury remains uncertain.

Time-resolved phosphoproteome and proteome analysis reveals kinase signaling on master transcription factors during myogenesis.

Myogenesis is governed by signaling networks that are tightly regulated in a time-dependent manner. Although different protein kinases have been identified, knowledge of the global signaling networks and their downstream substrates during myogenesis remains incomplete. Here, we map the myogenic differentiation of C2C12 cells using phosphoproteomics and proteomics. From these data, we infer global kinase activity and predict the substrates that are involved in myogenesis. We found that multiple mitogen-activated protein kinases (MAPKs) mark the initial wave of signaling cascades. Further phosphoproteomic and proteomic profiling with MAPK1/3 and MAPK8/9 specific inhibitions unveil their shared and distinctive roles in myogenesis. Lastly, we identified and validated the transcription factor nuclear factor 1 X-type (NFIX) as a novel MAPK1/3 substrate and demonstrated the functional impact of NFIX phosphorylation on myogenesis. Altogether, these data characterize the dynamics, interactions, and downstream control of kinase signaling networks during myogenesis on a global scale.

ß-Hydroxy-ß-methylbutyrate (HMB) supplementation and functional outcomes in multi-trauma patients: a study protocol for a pilot randomised clinical trial (BOOST trial).

BACKGROUND: There are no therapies proven to diminish the muscle wasting that occurs in patients after major trauma who are admitted to the intensive care unit (ICU). ß-Hydroxy-ß-methylbutyrate (HMB) is a nutrition intervention that may attenuate muscle loss and, thereby, improve recovery. The primary aim of this study is to determine the feasibility of a blinded randomised clinical trial of HMB supplementation to patients after major trauma who are admitted to the ICU. Secondary aims are to establish estimates for the impact of HMB when compared to placebo on muscle mass and nutrition-related patient outcomes. METHODS: This prospective, single-centre, blinded, randomised, placebo-controlled, parallel-group, feasibility trial with allocation concealment will recruit 50 participants over 18 months. After informed consent, participants will be randomised [1:1] to receive either the intervention (three grams of HMB dissolved in either 150 ml of orange juice for those allowed oral intake or 150 ml of water for those being enterally fed) or placebo (150 ml of orange juice for those allowed oral intake or 150 ml of water for those being enterally fed). The intervention will be commenced in ICU, continued after ICU discharge and ceased at hospital discharge or day 28 post randomisation, whichever occurs first. The primary outcome is the feasibility of administering the intervention. Secondary outcomes include change in muscle thickness using ultrasound and other nutritional and patient-centred outcomes. DISCUSSION: This study aims to determine the feasibility of administering HMB to critically ill multi-trauma patients throughout ICU admission until hospital discharge. Results will inform design of a larger randomised clinical trial. TRIAL REGISTRATION: The protocol is registered with Australian New Zealand Clinical Trials Registry (ANZCTR) ANZCTR: 12620001305910 . UTN: U1111-1259-5534.

Albumin and C-reactive protein relate to functional and body composition parameters in patients admitted to geriatric rehabilitation after acute hospitalization: findings from the RESORT cohort.

PURPOSE: Albumin and C-reactive protein (CRP) are non-specific markers of inflammation, which could affect muscle tissue during acute hospitalization. We investigated the association between albumin and CRP during acute hospitalization with functional and body composition parameters in patients admitted to geriatric rehabilitation. METHODS: The REStORing Health of Acutely Unwell AdulTs (RESORT) cohort includes geriatric rehabilitation patients assessed for change in activities of daily living (ADL, using the Katz index) during acute hospitalization, and subsequently for Katz ADL, gait speed (GS), handgrip strength (HGS) and skeletal muscle mass index (SMI) at geriatric rehabilitation admission. Albumin and CRP average (median), variation (interquartile range), and maximum or minimum were collected from serum samples, and were examined for their association with functional and body composition parameters using multivariable linear regression analysis adjusted for age, sex and length of acute hospital stay. RESULTS: 1769 Inpatients were included for analyses (mean age 82.6 years ± 8.1, 56% female). Median length of acute hospitalization was 7 [IQR 4, 13] days and median number of albumin and CRP measurements was 5 [IQR 3, 12] times. ADL declined in 89% of patients (median - 3 points, IQR - 4, - 2). Lower average albumin, higher albumin variation and lower minimum albumin were associated with larger declines in ADL and with lower ADL, GS, HGS and SMI at geriatric rehabilitation admission. Higher average and maximum CRP were associated with lower GS. CONCLUSION: Inflammation, especially lower albumin concentrations, during acute hospitalization is associated with lower physical function at geriatric rehabilitation admission.