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Key pointsr Five days of bed rest resulted in a reduction in leg lean mass and strength in older adults. r After bed rest, older (but not younger) adults had reduced amino acid-induced anabolic sensitivity (blunted muscle protein synthesis; MPS) and enhanced markers associated with the ubiquitin proteasome and autophagy-lysosomal systems (increase in molecular markers related to muscle proteolysis).r Younger adults did not lose leg lean mass (via DXA) after 5 days of bed rest despite blunted amino acid-induced mTORC1 signalling and increased skeletal muscle REDD1, REDD2 and MURF1 mRNA expression.r Exercise rehabilitation restored bed rest-induced deficits in lean mass, strength, nutrient-induced protein anabolism (protein synthesis and mTORC1 signalling) and select muscle proteolytic markers in older adults.Abstract Bed rest-induced muscle loss and impaired muscle recovery may contribute to age-related sarcopenia. It is unknown if there are age-related differences in muscle mass and muscle anabolic and catabolic responses to bed rest. A secondary objective was to determine if rehabilitation could reverse bed rest responses. Nine older and fourteen young adults participated in a 5-day bed rest challenge (BED REST). This was followed by 8 weeks of high intensity resistance exercise (REHAB). Leg lean mass (via dual-energy X-ray absorptiometry; DXA) and strength were determined. Muscle biopsies were collected during a constant stable isotope infusion in the postabsorptive state and after essential amino acid (EAA) ingestion on three occasions: before (PRE), after bed rest and after rehabilitation. Samples were assessed for protein synthesis, mTORC1 signalling, REDD1/2 expression and molecular markers related to muscle proteolysis (MURF1, MAFBX, AMPKα, LC3II/I, Beclin1). We found that leg lean mass and strength decreased in older but not younger adults after bedrest (P < 0.05) and was restored after rehabilitation. EAA-induced mTORC1 signalling and protein synthesis increased before bed rest in both age groups (P < 0.05). Although both groups had blunted mTORC1 signalling, increased REDD2 and MURF1 mRNA after bedrest, only older adults had reduced EAA-induced protein synthesis rates and increased MAFBX mRNA, p-AMPKα and the LC3II/I ratio (P < 0.05). We conclude that older adults are more susceptible than young persons to muscle loss after short-term bed rest. This may be partially explained by a combined suppression of protein synthesis and a marginal increase in proteolytic markers. Finally, rehabilitation restored bed rest-induced deficits in lean mass and strength in older adults.

IntroductionRecent studies have shown that vitamin-D intake can improve skeletal muscle function and strength in frail vitamin-D insufficient individuals. We investigated whether vitamin-D intake can improve the muscular response to resistance training in healthy young and elderly individuals, respectively.MethodsHealthy untrained young (n = 20, age 20–30) and elderly (n = 20, age 60–75) men were randomized to 16 weeks of daily supplementary intake of either 48 μg of vitamin-D + 800 mg calcium (Vitamin-D-group) or 800 mg calcium (Placebo-group) during a period and at a latitude of low sunlight (December-April, 56°N). During the last 12 weeks of the supplementation the subjects underwent progressive resistance training of the quadriceps muscle. Muscle hypertrophy, measured as changes in cross sectional area (CSA), and isometric strength of the quadriceps were determined. Muscle biopsies were analyzed for fiber type morphology changes and mRNA expression of vitamin-D receptor (VDR), cytochrome p450 27B1 (CYP27B1) and Myostatin.ResultsIn the vitamin-D groups, serum 25(OH)D concentration increased significantly and at week 12 was significantly different from placebo in both young men (71.6 vs. 50.4 nmol/L, respectively) and elderly men (111.2 vs. 66.7 nmol/L, respectively). After 12 weeks of resistance training, quadriceps CSA and isometric strength increased compared to baseline in young (CSA p < 0.0001, strength p = 0.005) and elderly (CSA p = 0.001, strength p < 0.0001) with no difference between vitamin-D and placebo groups. Vitamin-D intake and resistance training increased strength/CSA in elderly compared to young (p = 0.008). In the young vitamin-D group, the change in fiber type IIa percentage was greater after 12 weeks training (p = 0.030) and Myostatin mRNA expression lower compared to the placebo group (p = 0.006). Neither resistance training nor vitamin-D intake changed VDR mRNA expression.ConclusionNo additive effect of vitamin-D intake during 12 weeks of resistance training could be detected on either whole muscle hypertrophy or muscle strength, but improved muscle quality in elderly and fiber type morphology in young were observed, indicating an effect of vitamin-D on skeletal muscle remodeling.Trial registrationClinicalTrials with nr. NCT01252381Electronic supplementary materialThe online version of this article (doi:10.1186/s12986-015-0029-y) contains supplementary material, which is available to authorized users.

BackgroundSkeletal muscle mass is controlled by myostatin and Akt-dependent signaling on mammalian target of rapamycin (mTOR), glycogen synthase kinase 3β (GSK3β) and forkhead box O (FoxO) pathways, but it is unknown how these pathways are regulated in critically ill human muscle. To describe factors involved in muscle mass regulation, we investigated the phosphorylation and expression of key factors in these protein synthesis and breakdown signaling pathways in thigh skeletal muscle of critically ill intensive care unit (ICU) patients compared with healthy controls.Methodology/Principal FindingsICU patients were systemically inflamed, moderately hyperglycemic, received insulin therapy, and showed a tendency to lower plasma branched chain amino acids compared with controls. Using Western blotting we measured Akt, GSK3β, mTOR, ribosomal protein S6 kinase (S6k), eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), and muscle ring finger protein 1 (MuRF1); and by RT-PCR we determined mRNA expression of, among others, insulin-like growth factor 1 (IGF-1), FoxO 1, 3 and 4, atrogin1, MuRF1, interleukin-6 (IL-6), tumor necrosis factor α (TNF-α) and myostatin. Unexpectedly, in critically ill ICU patients Akt-mTOR-S6k signaling was substantially higher compared with controls. FoxO1 mRNA was higher in patients, whereas FoxO3, atrogin1 and myostatin mRNAs and MuRF1 protein were lower compared with controls. A moderate correlation (r2 = 0.36, p<0.05) between insulin infusion dose and phosphorylated Akt was demonstrated.Conclusions/SignificanceWe present for the first time muscle protein turnover signaling in critically ill ICU patients, and we show signaling pathway activity towards a stimulation of muscle protein synthesis and a somewhat inhibited proteolysis.

The present study investigated whether well-tolerated light-load resistance exercise (LL-RE) affects skeletal muscle fractional synthetic rate (FSR) and anabolic intracellular signaling as a way to counteract age-related loss of muscle mass. Untrained healthy elderly (>65-yr-old) men were subjected to 13 h of supine rest. After 2.5 h of rest, unilateral LL-RE, consisting of leg extensions (10 sets, 36 repetitions) at 16% of 1 repetition maximum (RM), was conducted. Subsequently, the subjects were randomized to oral intake of 4 g of whey protein per hour (PULSE, = 10), 28 g of whey protein at 0 h and 12 g of whey protein at 7 h postexercise (BOLUS, = 10), or 4 g of maltodextrin per hour (placebo, = 10). Quadriceps muscle biopsies were taken at 0, 3, 7, and 10 h postexercise from the resting and the exercised leg of each subject. Myofibrillar FSR and activity of select targets from the mechanistic target of rapamycin complex 1-signaling cascade were analyzed from the biopsies. LL-RE increased myofibrillar FSR compared with the resting leg throughout the 10-h postexercise period. Phosphorylated (T308) AKT expression increased in the exercised leg immediately after exercise. This increase persisted in the placebo group only. Levels of phosphorylated (T37/46) eukaryotic translation initiation factor 4E-binding protein 1 increased throughout the postexercise period in the exercised leg in the placebo and BOLUS groups and peaked at 7 h. In all three groups, phosphorylated (T56) eukaryotic elongation factor 2 decreased in response to LL-RE. We conclude that resistance exercise at only 16% of 1 RM increased myofibrillar FSR, irrespective of nutrient type and feeding pattern, which indicates an anabolic effect of LL-RE in elderly individuals. This finding was supported by increased signaling for translation initiation and translation elongation in response to LL-RE.

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Whey and caseinate were equally superior to control in the 6-h recovery period and displayed temporal differences with whey having a fast and superior effect in the early part of the recovery period. Effects on mRNA expressions indicate different regulatory mechanisms on the ubiquitin ligases MuRF1 and Atrogin1 in recovery from heavy resistance exercise.

Phenylalanine stable isotope tracer labeling of cow milk and meat and human experimental applications to study dietary protein-derived amino acid availability', Clinical Nutrition.