Kanagaraj Marimuthu

Chronic oral ingestion of l‐carnitine and carbohydrate increases muscle carnitine content and alters muscle fuel metabolism during exercise in humans

Non‐technical summary After 30 years of endeavour, this is the first study to show that muscle carnitine content can be increased in humans by dietary means and, perhaps more importantly, that carnitine plays a dual role in skeletal muscle fuel metabolism that is exercise intensity dependent. Specifically, we have shown that increasing muscle total carnitine content reduces muscle carbohydrate use during low intensity exercise, consistent with an increase in muscle lipid utilisation. However, during high intensity exercise muscle carnitine loading results in a better matching of glycolytic, pyruvate dehydrogenase complex and mitochondrial flux, thereby reducing muscle anaerobic energy generation. Collectively, these metabolic effects resulted in a reduced perception of effort and increased work output during a validated exercise performance test. These findings have significant implications for athletic performance and pathophysiological conditions where fat oxidation is impaired or anaerobic ATP production is increased during exercise.

A meta-analysis of the effect of combinations of immune modulating nutrients on outcome in patients undergoing major open gastrointestinal surgery

Background:Immune modulating nutrition (IMN) has been shown to reduce complications after major surgery, but strong evidence to recommend its routine use is still lacking. Objective:The aim of this meta-analysis was to evaluate the impact of IMN combinations on postoperative infectious and noninfectious complications, length of hospital stay, and mortality in patients undergoing major open gastrointestinal surgery. Methods:Randomized controlled trials published between January 1980 and February 2011 comparing isocaloric and isonitrogenous enteral IMN combinations with standard diet in patients undergoing major open gastrointestinal surgery were included. The quality of evidence and strength of recommendation for each postoperative outcome were assessed using the GRADE approach and the outcome measures were analyzed with RevMan 5.1 software (Cochrane Collaboration, Copenhagen, Denmark). Results:Twenty-six randomized controlled trials enrolling 2496 patients (1252 IMN and 1244 control) were included. The meta-analysis suggests strong evidence in support of decrease in the incidence of postoperative infectious [risk ratio (RR) (95% confidence interval [CI]): 0.64 (0.55, 0.74)] and length of hospital stay [mean difference (95% CI): −1.88 (−2.91, −0.84 days)] in those receiving IMN. Even though significant benefit was observed for noninfectious complications [RR (95% CI): 0.82 (0.71, 0.95)], the quality of evidence was low. There was no statistically significant benefit on mortality [RR (95% CI): 0.83 (0.49, 1.41)]. Conclusions:IMN is beneficial in reducing postoperative infectious and noninfectious complications and shortening hospital stay in patients undergoing major open gastrointestinal surgery.

Mechanisms regulating muscle mass during disuse atrophy and rehabilitation in humans

Muscle mass loss accompanies periods of bedrest and limb immobilization in humans and requires rehabilitation exercise to effectively restore mass and function. Although recent evidence points to an early and transient rise in muscle protein breakdown contributing to this decline in muscle mass, the driving factor seems to be a reduction in muscle protein synthesis, not least in part due to the development of anabolic resistance to amino acid provision. Although the AKT signaling pathway has been identified in small animals as central to the regulation of muscle protein synthesis, several studies in humans have now demonstrated a disassociation between AKT signaling and muscle protein synthesis during feeding, exercise, and immobilization, suggesting that the mechanisms regulating protein synthesis in human skeletal muscle are more complex than initially thought (at least in non-inflammatory states). During rehabilitation, exercise-induced myogenesis may in part be responsible for the recovery of muscle mass. Rapid and sustained exercise-induced suppression of myostatin mRNA expression, that precedes any gain in muscle mass, points to this, along with other myogenic proteins, as being potential regulators of muscle regeneration during exercise rehabilitation in humans.

Skeletal muscle carnitine loading increases energy expenditure, modulates fuel metabolism gene networks and prevents body fat accumulation in humans

•  Carnitine is a substrate for the carnitine palmitoyltransferase 1 enzyme, a rate‐limiting step in fatty acid oxidation within skeletal muscle. •  Insulin stimulates carnitine transport into skeletal muscle. •  A 20% increase in muscle carnitine content, achieved via 12 weeks of twice daily supplementation of a beverage containing 1.36 g of l‐carnitine and 80 g of carbohydrate (in order to stimulate insulin‐mediated muscle carnitine transport), prevented an 18% increase in body fat mass associated with carbohydrate supplementation alone in healthy young men. •  A novel finding of the present study was that this prevention of fat gain was associated with a greater energy expenditure and fat oxidation during low‐intensity physical activity, and an adaptive increase in expression of gene networks involved in muscle insulin signalling and fatty acid metabolism. •  Implications to health warrant further investigation, particularly in obese individuals who have a reduced reliance on muscle fat oxidation during exercise.

Obesity appears to be associated with altered muscle protein synthetic and breakdown responses to increased nutrient delivery in older men, but not reduced muscle mass or contractile function.

Obesity is increasing, yet despite the necessity of maintaining muscle mass and function with age, the effect of obesity on muscle protein turnover in older adults remains unknown. Eleven obese (BMI 31.9 ± 1.1 kg · m−2) and 15 healthy-weight (BMI 23.4 ± 0.3 kg · m−2) older men (55–75 years old) participated in a study that determined muscle protein synthesis (MPS) and leg protein breakdown (LPB) under postabsorptive (hypoinsulinemic-euglycemic clamp) and postprandial (hyperinsulinemic hyperaminoacidemic-euglycemic clamp) conditions. Obesity was associated with systemic inflammation, greater leg fat mass, and patterns of mRNA expression consistent with muscle deconditioning, whereas leg lean mass, strength, and work done during maximal exercise were no different. Under postabsorptive conditions, MPS and LPB were equivalent between groups, whereas insulin and amino acid administration increased MPS in only healthy-weight subjects and was associated with lower leg glucose disposal (LGD) (63%) in obese men. Blunting of MPS in the obese men was offset by an apparent decline in LPB, which was absent in healthy-weight subjects. Lower postprandial LGD in obese subjects and blunting of MPS responses to amino acids suggest that obesity in older adults is associated with diminished muscle metabolic quality. This does not, however, appear to be associated with lower leg lean mass or strength.

Transient transcriptional events in human skeletal muscle at the outset of concentric resistance exercise training

We sought to ascertain the time course of transcriptional events that occur in human skeletal muscle at the outset of resistance exercise (RE) training in RE naive individuals and determine whether the magnitude of response was associated with exercise-induced muscle damage. Sixteen RE naive men were recruited; eight underwent two sessions of 5 × 30 maximum isokinetic knee extensions (180°/s) separated by 48 h. Muscle biopsies of the vastus lateralis, obtained from different sites, were taken at baseline and 24 h after each exercise bout. Eight individuals acted as nonexercise controls with biopsies obtained at the same time intervals. Transcriptional changes were assessed by microarray and protein levels of heat shock protein (HSP) 27 and αB-crystallin in muscle cross sections by immunohistochemistry as a proxy measure of muscle damage. In control subjects, no probe sets were significantly altered (false discovery rate < 0.05), and HSP27 and αB-crystallin protein remained unchanged throughout the study. In exercised subjects, significant intersubject variability following the initial RE bout was observed in the muscle transcriptome, with greatest changes occurring in subjects with elevated HSP27 and αB-crystallin protein. Following the second bout, the transcriptome response was more consistent, revealing a cohort of probe sets associated with immune activation, the suppression of oxidative metabolism, and ubiquitination, as differentially regulated. The results reveal that the initial transcriptional response to RE is variable in RE naive volunteers, potentially associated with muscle damage and unlikely to reflect longer term adaptations to RE training. These results highlight the importance of considering multiple time points when determining the transcriptional response to RE and associated physiological adaptation.

Statin myalgia is not associated with reduced muscle strength, mass or protein turnover in older male volunteers, but is allied with a slowing of time to peak power output, insulin resistance and differential muscle mRNA expression

Statins cause muscle‐specific side effects, most commonly muscle aches/weakness (myalgia), particularly in older people. Furthermore, evidence has linked statin use to increased risk of type 2 diabetes. However, the mechanisms involved are unknown. This is the first study to measure muscle protein turnover rates and insulin sensitivity in statin myalgic volunteers and age‐matched, non‐statin users under controlled fasting and fed conditions using gold standard methods. We demonstrate in older people that chronic statin myalgia is not associated with deficits in muscle strength and lean mass or the dysregulation of muscle protein turnover compared to non‐statin users. Furthermore, there were no between‐group differences in blood or muscle inflammatory markers. Statin users did, however, show blunting of muscle power output at the onset of dynamic exercise, increased abdominal adiposity, whole body and leg insulin resistance, and clear differential expression of muscle genes linked to mitochondrial dysfunction and apoptosis, which warrant further investigation.

Vegetarians have a reduced skeletal muscle carnitine transport capacity

BACKGROUND Ninety-five percent of the body carnitine pool resides in skeletal muscle where it plays a vital role in fuel metabolism. However, vegetarians obtain negligible amounts of carnitine from their diet. OBJECTIVE We tested the hypothesis that muscle carnitine uptake is elevated in vegetarians compared with that in nonvegetarians to maintain a normal tissue carnitine content. DESIGN Forty-one young (aged ≈22 y) vegetarian and nonvegetarian volunteers participated in 2 studies. The first study consisted of a 5-h intravenous infusion of l-carnitine while circulating insulin was maintained at a physiologically high concentration (≈170 mU/L; to stimulate muscle carnitine uptake) or at a fasting concentration (≈6 mU/L). The second study consisted of oral ingestion of 3 g l-carnitine. RESULTS Basal plasma total carnitine (TC) concentration, 24-h urinary TC excretion, muscle TC content, and muscle carnitine transporter [organic cation transporter 2 (OCTN2)] messenger RNA and protein expressions were 16% (P < 0.01), 58% (P < 0.01), 17% (P < 0.05), 33% (P < 0.05), and 37% (P = 0.09) lower, respectively, in vegetarian volunteers. However, although nonvegetarians showed a 15% increase (P < 0.05) in muscle TC during l-carnitine infusion with hyperinsulinemia, l-carnitine infusion in the presence or absence of hyperinsulinemia had no effect on muscle TC content in vegetarians. Nevertheless, 24-h urinary TC excretion was 55% less in vegetarians after l-carnitine ingestion. CONCLUSIONS Vegetarians have a lower muscle TC and reduced capacity to transport carnitine into muscle than do nonvegetarians, possibly because of reduced muscle OCTN2 content. Thus, the greater whole-body carnitine retention observed after a single dose of l-carnitine in vegetarians was not attributable to increased muscle carnitine storage.

Acute pantothenic acid and cysteine supplementation does not affect muscle coenzyme A content, fuel selection, or exercise performance in healthy humans

Reduced skeletal muscle free coenzyme A (CoASH) availability may decrease the contribution of fat oxidation to ATP production during high-intensity, submaximal exercise or, alternatively, limit pyruvate dehydrogenase complex (PDC) flux and thereby carbohydrate oxidation. Here we attempted to increase the muscle CoASH pool in humans, via pantothenic acid and cysteine feeding, in order to elucidate the role of CoASH availability on muscle fuel metabolism during exercise. On three occasions, eight healthy male volunteers (age 22.9 ± 1.4 yr, body mass index 24.2 ± 1.5 kg/m(2)) cycled at 75% maximal oxygen uptake (Vo(2max)) to exhaustion, followed by a 15-min work output performance test. Muscle biopsies were obtained at rest, and after 60 min and 91.3 ± 3.1 min of exercise (time to exhaustion on baseline visit) on each occasion. Two weeks following the first visit (baseline), 1 wk of oral supplementation with either 3 g/day of a placebo control (glucose polymer; CON) or 1.5 g/day each of d-pantothenic acid and l-cysteine (CP) was carried out prior to the second and third visits in a randomized, counterbalanced, double-blind manner, leaving a 3-wk gap in total between each visit. Resting muscle CoASH content was not altered by supplementation in any visit. Following 60 min of exercise, muscle CoASH content was reduced by 13% from rest in all three visits (P < 0.05), and similar changes in the respiratory exchange ratio, glycogenolysis (∼235 mmol/kg dry muscle), PCr degradation (∼57 mmol/kg dry muscle), and lactate (∼25 mmol/kg dry muscle) and acetylcarnitine (∼12 mmol(.)kg/dry muscle) accumulation was observed during exercise when comparing visits. Furthermore, no difference in work output was observed when comparing CON and CP. Acute feeding with pantothenic acid and cysteine does not alter muscle CoASH content and consequently does not impact on muscle fuel metabolism or performance during exercise in humans.

Consequences of Late-Stage Non–Small-Cell Lung Cancer Cachexia on Muscle Metabolic Processes

Introduction: The loss of muscle is common in patients with advanced non–small‐cell lung cancer (NSCLC) and contributes to the high morbidity and mortality of this group. The exact mechanisms behind the muscle loss are unclear. Patients and Methods: To investigate this, 4 patients with stage IV NSCLC who met the clinical definitions for sarcopenia and cachexia were recruited, along with 4 age‐matched healthy volunteers. After an overnight fast, biopsy specimens were obtained from the vastus lateralis, and the key components associated with inflammation and the control of muscle protein, carbohydrate, and fat metabolism were assessed. Results: Compared with the healthy volunteers, significant increases in mRNA levels for interleukin‐6 and NF‐&kgr;B signaling and lower intramyocellular lipid content in slow‐twitch fibers were observed in NSCLC patients. Although a significant decrease in phosphorylation of the mechanistic target of rapamycin (mTOR) signaling protein 4E‐BP1 (Ser65) was observed, along with a trend toward reduced p70 S6K (Thr389) phosphorylation (P = .06), no difference was found between groups for the mRNA levels of MAFbx (muscle atrophy F box) and MuRF1 (muscle ring finger protein 1), chymotrypsin‐like activity of the proteasome, or protein levels of multiple proteasome subunits. Moreover, despite decreases in intramyocellular lipid content, no robust changes in mRNA levels for key proteins involved in insulin signaling, glycolysis, oxidative metabolism, or fat metabolism were observed. Conclusion: These findings suggest that examining the contribution of suppressed mTOR signaling in the loss of muscle mass in late‐stage NSCLC patients is warranted and reinforces our need to understand the potential contribution of impaired fat metabolism and muscle protein synthesis in the etiology of cancer cachexia. Micro‐Abstract: Muscle loss is common in advanced lung cancer, impairing quality of life and shortening life expectancy. The impact of cancer on muscle metabolism has not been well explored. The effects of late‐stage non–small‐cell lung cancer on key metabolic processes in muscle was studied. Changes consistent with impaired synthesis of new muscle proteins and reduced lipid storage were observed.