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The role of dysregulated intracellular creatine (Cr) metabolism in disuse atrophy is unknown. In this study, skeletal muscle biopsy samples were obtained after 7 days of unilateral leg immobilization (IMMOB) and from the nonimmobilized control limb (CTRL) of 15 healthy men (23.1 ± 3.5 yr). Samples were analyzed for fiber type cross-sectional area (CSA) and creatine transporter (CreaT) at the cell membrane periphery (MEM) or intracellular (INT) areas, via immunofluorescence microscopy. Creatine kinase (CK) and AMP-activated protein kinase (AMPK) were determined via immunoblot. Phosphocreatine (PCr), Cr, and ATP were measured via enzymatic analysis. Body composition and maximal isometric knee extensor strength were assessed before and after disuse. Leg strength and fat-free mass were reduced in IMMOB (~32% and 4%, respectively; P < 0.01 for both). Type II fiber CSA was smaller (~12%; P = 0.028) and intramuscular PCr lower (~13%; P = 0.015) in IMMOB vs. CTRL. CreaT protein was greater in type I fibers in both limbs ( P < 0.01). CreaT was greater in IMMOB vs. CTRL ( P < 0.01) and inversely associated with PCr concentration in both limbs ( P < 0.05). MEM CreaT was greater than INT CreaT in type I and II fibers of both limbs (~14% for both; P < 0.01 for both). Type I fiber CreaT tended to be greater in IMMOB vs. CTRL ( P = 0.074). CK was greater and phospho-to-total AMPKThr172tended to be greater,in IMMOB vs. CTRL ( P = 0.013 and 0.051, respectively). These findings suggest that modulation of intracellular Cr metabolism is an adaptive response to immobilization in young healthy skeletal muscle.

mTORC1 is an important regulator of muscle mass but how it is modulated by oxygen and nutrients is not completely understood. We show that loss of the prolyl hydroxylase domain isoform 1 oxygen sensor in mice (PHD1KO) reduces muscle mass. PHD1KO muscles show impaired mTORC1 activation in response to leucine whereas mTORC1 activation by growth factors or eccentric contractions was preserved. The ability of PHD1 to promote mTORC1 activity is independent of its hydroxylation activity but is caused by decreased protein content of the leucyl tRNA synthetase (LRS) leucine sensor. Mechanistically, PHD1 interacts with and stabilizes LRS. This interaction is promoted during oxygen and amino acid depletion and protects LRS from degradation. Finally, elderly subjects have lower PHD1 levels and LRS activity in muscle from aged versus young human subjects. In conclusion, PHD1 ensures an optimal mTORC1 response to leucine after episodes of metabolic scarcity., Nature Communications, 11, ISSN:2041-1723

Sarcopenia is of important clinical relevance for loss of independence in older adults. The prevalence of obesity in combination with sarcopenia (“sarcopenic-obesity”) is increasing at a rapid rate. However, whilst the development of sarcopenia is understood to be multi-factorial and harmful to health, the role of obesity from a protective and damaging perspective on skeletal muscle in aging, is poorly understood. Specifically, the presence of obesity in older age may be accompanied by a greater volume of skeletal muscle mass in weight-bearing muscles compared with lean older individuals, despite impaired physical function and resistance to anabolic stimuli. Collectively, these findings support a potential paradox in which obesity may protect skeletal muscle mass in older age. One explanation for these paradoxical findings may be that the anabolic response to weight-bearing activity could be greater in obese vs. lean older individuals due to a larger mechanical stimulus, compensating for the heightened muscle anabolic resistance. However, it is likely that there is a complex interplay between muscle, adipose, and external influences in the aging process that are ultimately harmful to health in the long-term. This narrative briefly explores some of the potential mechanisms regulating changes in skeletal muscle mass and function in aging combined with obesity and the interplay with sarcopenia, with a particular focus on muscle morphology and the regulation of muscle proteostasis. In addition, whilst highly complex, we attempt to provide an updated summary for the role of obesity from a protective and damaging perspective on muscle mass and function in older age. We conclude with a brief discussion on treatment of sarcopenia and obesity and a summary of future directions for this research field.

BACKGROUND Unavoidable periods of disuse lead to muscle atrophy and functional decline. Preventing such declines can reduce the risk of re-injury and improve recovery of normal physiological functioning. OBJECTIVES We aimed to determine the effectiveness of high-dose leucine supplementation on muscle morphology and strength during 7 d of unilateral lower-limb immobilization, and the role of myofibrillar (MyoPS) and mitochondrial (MitoPS) protein synthesis in disuse atrophy. METHODS Sixteen healthy males (mean ± SEM age: 23 ± 1 y) underwent 7 d of unilateral lower-limb immobilization, with thrice-daily leucine (LEU; n = 8) or placebo (PLA; n = 8) supplementation (15 g/d). Before and after immobilization, muscle strength and compartmental tissue composition were assessed. A primed continuous infusion of l-[ring-13C6]-phenylalanine with serial muscle biopsies was used to determine postabsorptive and postprandial (20 g milk protein) MyoPS and MitoPS, fiber morphology, markers of protein turnover, and mitochondrial function between the control leg (CTL) and the immobilized leg (IMB). RESULTS Leg fat-free mass was reduced in IMB (mean ± SEM: -3.6% ± 0.5%; P = 0.030) but not CTL with no difference between supplementation groups. Isometric knee extensor strength declined to a greater extent in IMB (-27.9% ± 4.4%) than in CTL (-14.3% ± 4.4%; P = 0.043) with no difference between groups. In response to 20 g milk protein, postprandial MyoPS rates were significantly lower in IMB than in CTL (-22% ± 4%; P

With the continued increase in average life expectancy and a shift in population demographics towards that of an ageing society, the current and future anticipated challenge to health-care resources is unprecedented. Age-related muscle loss plays an essential role in the deterioration in strength, function, and predisposition to numerous comorbidities and a reduction in the quality of life. Alongside physical activity and exercise, the consumption of sufficient dietary protein in older age can assist in the maintenance of muscle mass and offset age-related comorbidities. However, older individuals require higher total daily and per meal dietary protein intakes to support muscle mass compared with younger individuals, but many do not achieve the required amount due to alterations in chewing capability, taste perception, appetite (i.e. during hospitalisation), psycho-social factors (i.e. loneliness), poverty, and gastrointestinal disorders. In such cases where dietary protein amount may be limited, protein quality undoubtedly plays a vital role in supporting muscle health in older age. Protein quality for muscle health is largely determined by the abundance, and availability upon digestion, of essential (or indispensable) amino acids. In this regard, animal-based protein sources are generally considered to be of higher quality than plant-based proteins. Due to the reported barriers to the consumption of some animal-protein sources in older adults, dairy-based proteins offer an attractive means to ensure that sufficient protein for muscle health is consumed at each main meal, and possibly at mid-meal snacks. Indeed, metaanalyses and randomised controlled trials all provide strong support for the muscle benefits of dairy protein supplementation in older age. Importantly, whole-food dairy sources (yoghurt, cheeses, full-fat milk) may offer muscle health benefits similar, or perhaps even additional, to isolated dairy sources traditionally consumed in the form of whey or casein supplements. Herein, we outline the strong evidence base for dairy protein consumption for muscle health in older age, and provide clear, pragmatic, and safe guidance on how dairy protein nutritional strategies can be implemented in this population.

Maintaining adequate daily protein intake is important to maintain muscle mass throughout the lifespan. In this regard, the overnight period has been identified as a window of opportunity to increase protein intake in the elderly. However, it is unknown whether pre-sleep protein intake affects next-morning appetite and, consequently, protein intake. Therefore, the purpose of the current study was to investigate the effects of a pre-sleep protein drink on next-morning appetite, energy intake and metabolism. Twelve older individuals (eight males, four females, age: 71.3 &plusmn, 4.2 years) took part in a single-blind randomised cross-over study. After a standardised dinner, participants consumed either a 40-g protein drink, isocaloric maltodextrin drink, or placebo water control before bedtime. Next-morning appetite, energy intake, resting metabolic rate (RMR), respiratory exchange rate (RER), and plasma acylated ghrelin, leptin, glucose, and insulin concentrations were assessed. No between-group differences were observed for appetite and energy intake at breakfast. Furthermore, RMR, RER, and assessed blood markers were not significantly different between any of the treatment groups. Pre-sleep protein intake does not affect next-morning appetite and energy intake and is therefore a viable strategy to increase daily protein intake in an older population.

New Findings What is the central question of this study? Does shorter rest between sets of resistance exercise promote a superior circulating hormonal and acute muscle anabolic response compared with longer rest periods? What is the main finding and its importance? We demonstrate that short rest (1 min) between sets of moderate-intensity, high-volume resistance exercise blunts the acute muscle anabolic response compared with a longer rest period (5 min), despite a superior circulating hormonal milieu. These data have important implications for the development of training regimens to maximize muscle hypertrophy. Manipulating the rest-recovery interval between sets of resistance exercise may influence training-induced muscle remodelling. The aim of this study was to determine the acute muscle anabolic response to resistance exercise performed with short or long inter-set rest intervals. In a study with a parallel-group design, 16 males completed four sets of bilateral leg-press and knee-extension exercise at 75% of one-repetition maximum to momentary muscular failure, followed by ingestion of 25 g of whey protein. Resistance exercise sets were interspersed by 1 min (n = 8) or 5 min of passive rest (n = 8). Muscle biopsies were obtained at rest, 0, 4, 24 and 28 h postexercise during a primed continuous infusion of l-[ring-13C6]phenylalanine to determine myofibrillar protein synthesis and intracellular signalling. We found that the rate of myofibrillar protein synthesis increased above resting values from 0 to 4 h postexercise with 1 (76%; P = 0.047) and 5 min inter-set rest (152%; P

Obesity is recognised as a risk factor for many types of cancers, in particular hepatocellular carcinoma (HCC). A critical factor in the development of HCC from non-alcoholic fatty liver disease (NAFLD) is the presence of non-alcoholic steatohepatitis (NASH). Therapies aimed at NASH to reduce the risk of HCC are sparse and largely unsuccessful. Lifestyle modifications such as diet and regular exercise have poor adherence. Moreover, current pharmacological treatments such as pioglitazone and vitamin E have limited effects on fibrosis, a key risk factor in HCC progression. As NAFLD is becoming more prevalent in developed countries due to rising rates of obesity, a need for directed treatment is imperative. Numerous novel therapies including PPAR agonists, anti-fibrotic therapies and agents targeting inflammation, oxidative stress and the gut-liver axis are currently in development, with the aim of targeting key processes in the progression of NASH and HCC. Here, we critically evaluate literature on the aetiology of NAFLD-related HCC, and explore the potential treatment options for NASH and HCC.

Preserving skeletal muscle mass and functional capacity is essential for healthy ageing. Transient periods of disuse and/or inactivity in combination with sub-optimal dietary intake have been shown to accelerate the age-related loss of muscle mass and strength, predisposing to disability and metabolic disease. Mechanisms underlying disuse and/or inactivity-related muscle deterioration in the older adults, whilst multifaceted, ultimately manifest in an imbalance between rates of muscle protein synthesis and breakdown, resulting in net muscle loss. To date, the most potent intervention to mitigate disuse-induced muscle deterioration is mechanical loading in the form of resistance exercise. However, the feasibility of older individuals performing resistance exercise during disuse and inactivity has been questioned, particularly as illness and injury may affect adherence and safety, as well as accessibility to appropriate equipment and physical therapists. Therefore, optimising nutritional intake during disuse events, through the introduction of protein-rich whole-foods, isolated proteins and nutrient compounds with purported pro-anabolic and anti-catabolic properties could offset impairments in muscle protein turnover and, ultimately, the degree of muscle atrophy and recovery upon re-ambulation. The current review therefore aims to provide an overview of nutritional countermeasures to disuse atrophy and anabolic resistance in older individuals.

Context: A diminished muscle anabolic response to protein nutrition may underpin age-associated muscle loss. Objective: To determine how chronological and biological aging influence myofibrillar protein synthesis (MyoPS). Design: Cross-sectional comparison. Setting: Clinical research facility. Participants: Ten older lean [OL: 71.7 ± 6 years; body mass index (BMI) ≤25 kg ⋅ m−2], 7 older obese (OO: 69.1 ± 2 years; BMI ≥30 kg ⋅ m−2), and 18 young lean (YL) individuals (25.5 ± 4 years; BMI ≤25 kg ⋅ m−2). Intervention: Skeletal muscle biopsies obtained during a primed-continuous infusion of l-[ring-13C6]-phenylalanine. Main Outcome Measures: Anthropometrics, insulin resistance, inflammatory markers, habitual diet, physical activity, MyoPS rates, and fiber-type characteristics. Results: Fat mass, insulin resistance, inflammation, and type II fiber intramyocellular lipid were greater, and daily step count lower, in OO compared with YL and OL. Postprandial MyoPS rates rose above postabsorptive values by ∼81% in YL (P < 0.001), ∼38% in OL (P = 0.002, not different from YL), and ∼9% in OO (P = 0.11). Delta change in postprandial MyoPS from postabsorptive values was greater in YL compared with OL (P = 0.032) and OO (P < 0.001). Absolute postprandial MyoPS rates and delta postprandial MyoPS change were associated with step count (r2 = 0.33; P = 0.015) and leg fat mass (r2 = 0.4; P = 0.006), respectively, in older individuals. Paradoxically, lean mass was similar between groups, and muscle fiber area was greater in OO vs OL (P = 0.002). Conclusion: Age-related muscle anabolic resistance is exacerbated in obese inactive individuals, with no apparent detriment to muscle mass., We studied how chronological and biological aging influence muscle anabolism and found that nutrient-stimulated muscle protein synthesis rates are impaired in obese, inactive older individuals.

What is the central question of this study? Does shorter rest between sets of resistance exercise promote a superior circulating hormonal and acute muscle anabolic response compared with longer rest periods? What is the main finding and its importance? We demonstrate that short rest (1 min) between sets of moderate-intensity, high-volume resistance exercise blunts the acute muscle anabolic response compared with a longer rest period (5 min), despite a superior circulating hormonal milieu. These data have important implications for the development of training regimens to maximize muscle hypertrophy. Manipulating the rest-recovery interval between sets of resistance exercise may influence training-induced muscle remodelling. The aim of this study was to determine the acute muscle anabolic response to resistance exercise performed with short or long inter-set rest intervals. In a study with a parallel-group design, 16 males completed four sets of bilateral leg-press and knee-extension exercise at 75% of one-repetition maximum to momentary muscular failure, followed by ingestion of 25 g of whey protein. Resistance exercise sets were interspersed by 1 min (n = 8) or 5 min of passive rest (n = 8). Muscle biopsies were obtained at rest, 0, 4, 24 and 28 h postexercise during a primed continuous infusion of l-[ring-(13) C6 ]phenylalanine to determine myofibrillar protein synthesis and intracellular signalling. We found that the rate of myofibrillar protein synthesis increased above resting values from 0 to 4 h postexercise with 1 (76%; P = 0.047) and 5 min inter-set rest (152%; P 0.001) and was significantly greater in the 5 min inter-set rest group (P = 0.001). Myofibrillar protein synthesis rates at 24-28 h postexercise remained elevated above resting values (P 0.05) and were indistinguishable between groups. Postexercise p70S6K(Thr389) and rpS6(Ser240/244) phosphorylation were reduced with 1 compared with 5 min inter-set rest, whereas phosphorylation of eEF2(Thr56) , TSC2(Thr1462) , AMPK(Thr172) and REDD1 protein were greater for 1 compared with 5 min inter-set rest. Serum testosterone was greater at 20-40 min postexercise and plasma lactate greater immediately postexercise for 1 versus 5 min inter-set rest. Resistance exercise with short (1 min) inter-set rest duration attenuated myofibrillar protein synthesis during the early postexercise recovery period compared with longer (5 min) rest duration, potentially through compromised activation of intracellular signalling.

Skeletal muscle mass plays a vital role in locomotion, whole-body metabolic health, and is a positive predictor of longevity. It is well established the mammalian target of rapamycin (mTOR) is a central regulator of skeletal muscle protein turnover. The pursuit to find novel nutrient compounds or functional food sources that possess the ability to activate mTOR and promote skeletal muscle protein accretion has been on going. Over the last decade, a key role has been proposed for the phospholipid phosphatidic acid (PA) in mTOR activation. Mechanical load-induced (i.e., resistance exercise) intramuscular PA can directly bind to and activate mTOR. In addition, PA provided exogenously in cell culture heightens mTOR activity, albeit indirectly. Thus, endogenously generated PA and exogenous provision of PA appear to act through distinct mechanisms that converge on mTOR and, potentially, may amplify muscle protein synthesis. In support of this notion, limited evidence from humans suggests that resistance exercise training combined with oral supplemental PA enhances strength gains and muscle hypertrophy. However, the precise mechanisms underpinning the augmented muscle remodelling response with supplemental PA remain elusive. In this review, we will critically examine available evidence from cell cultures and animal and human experimental models to provide an overview of the mechanisms through which endogenous and exogenous PA may act to promote muscle anabolism, and discuss the potential for PA as a therapeutic tool to maintain or restore skeletal muscle mass in the context of ageing and disease.