Background: Resistance exercise increases muscle mass and function in older adults, but responses are attenuated compared with younger people. Data suggest that long-chain n–3 polyunsaturated fatty acids (PUFAs) may enhance adaptations to resistance exercise in older women. To our knowledge, this possibility has not been investigated in men.Objective: We sought to determine the effects of long-chain n–3 PUFA supplementation on resistance exercise training–induced increases in muscle mass and function and whether these effects differ between older men and women.Design: Fifty men and women [men: n = 27, mean ± SD age: 70.6 ± 4.5 y, mean ± SD body mass index (BMI; in kg/m2): 25.6 ± 4.2; women: n = 23, mean ± SD age: 70.7 ± 3.3 y, mean ± SD BMI: 25.3 ± 4.7] were randomly assigned to either long-chain n–3 PUFA (n = 23; 3 g fish oil/d) or placebo (n = 27; 3 g safflower oil/d) and participated in lower-limb resistance exercise training twice weekly for 18 wk. Muscle size, strength, and quality (strength per unit muscle area), functional abilities, and circulating metabolic and inflammatory markers were measured before and after the intervention.Results: Maximal isometric torque increased after exercise training to a greater (P < 0.05) extent in the long-chain n–3 PUFA group than in the placebo group in women, with no differences (P > 0.05) between groups in men. In both sexes, the effect of exercise training on maximal isokinetic torque at 30, 90, and 240° s−1, 4-m walk time, chair-rise time, muscle anatomic cross-sectional area, and muscle fat did not differ (P > 0.05) between groups. There was a greater (P < 0.05) increase in muscle quality in women after exercise training in the long-chain n–3 PUFA group than in the placebo group, with no such differences in men (P > 0.05). Long-chain n–3 PUFAs resulted in a greater decrease (P < 0.05) than the placebo in plasma triglyceride concentrations in both sexes, with no differences (P > 0.05) in glucose, insulin, or inflammatory markers.Conclusion: Long-chain n–3 PUFA supplementation augments increases in muscle function and quality in older women but not in older men after resistance exercise training. This trial was registered at clinicaltrials.gov as NCT02843009.

The currently accepted amount of protein required to achieve maximal stimulation of myofibrillar protein synthesis (MPS) following resistance exercise is 20–25 g. However, the influence of lean body mass (LBM) on the response of MPS to protein ingestion is unclear. Our aim was to assess the influence of LBM, both total and the amount activated during exercise, on the maximal response of MPS to ingestion of 20 or 40 g of whey protein following a bout of whole‐body resistance exercise. Resistance‐trained males were assigned to a group with lower LBM (≤65 kg; LLBM n = 15) or higher LBM (≥70 kg; HLBM n = 15) and participated in two trials in random order. MPS was measured with the infusion of 13C6‐phenylalanine tracer and collection of muscle biopsies following ingestion of either 20 or 40 g protein during recovery from a single bout of whole‐body resistance exercise. A similar response of MPS during exercise recovery was observed between LBM groups following protein ingestion (20 g – LLBM: 0.048 ± 0.018%·h−1; HLBM: 0.051 ± 0.014%·h−1; 40 g – LLBM: 0.059 ± 0.021%·h−1; HLBM: 0.059 ± 0.012%·h−1). Overall (groups combined), MPS was stimulated to a greater extent following ingestion of 40 g (0.059 ± 0.020%·h−1) compared with 20 g (0.049 ± 0.020%·h−1; P = 0.005) of protein. Our data indicate that ingestion of 40 g whey protein following whole‐body resistance exercise stimulates a greater MPS response than 20 g in young resistance‐trained men. However, with the current doses, the total amount of LBM does not seem to influence the response.

Skeletal muscle is a plastic tissue capable of adapting and mal-adapting to physical activity and diet. The response of skeletal muscle to adaptive stimuli, such as exercise, can be modified by the prior nutritional status of the muscle. The influence of nutrition on skeletal muscle has the potential to substantially impact physical function and whole body metabolism. Animal and cell based models show that omega-3 fatty acids, in particular those of marine origin, can influence skeletal muscle metabolism. Furthermore, recent human studies demonstrate that omega-3 fatty acids of marine origin can influence the exercise and nutritional response of skeletal muscle. These studies show that the prior omega-3 status influences not only the metabolic response of muscle to nutrition, but also the functional response to a period of exercise training. Omega-3 fatty acids of marine origin therefore have the potential to alter the trajectory of a number of human diseases including the physical decline associated with aging. We explore the potential molecular mechanisms by which omega-3 fatty acids may act in skeletal muscle, considering the n-3/n-6 ratio, inflammation and lipidomic remodelling as possible mechanisms of action. Finally, we suggest some avenues for further research to clarify how omega-3 fatty acids may be exerting their biological action in skeletal muscle.

Using an amalgamation of previously studied “train‐low” paradigms, we tested the effects of reduced carbohydrate (CHO) but high leucine availability on cell‐signaling responses associated with exercise‐induced regulation of mitochondrial biogenesis and muscle protein synthesis (MPS). In a repeated‐measures crossover design, 11 males completed an exhaustive cycling protocol with high CHO availability before, during, and after exercise (HIGH) or alternatively, low CHO but high protein (leucine enriched) availability (LOW + LEU). Muscle glycogen was different (P < 0.05) pre‐exercise (HIGH: 583 ± 158, LOW + LEU: 271 ± 85 mmol kg−1 dw) but decreased (P < 0.05) to comparable levels at exhaustion (≈100 mmol kg−1 dw). Despite differences (P < 0.05) in exercise capacity (HIGH: 158 ± 29, LOW + LEU: 100 ± 17 min), exercise induced (P < 0.05) comparable AMPK α2 (3–4‐fold) activity, PGC‐1α (13‐fold), p53 (2‐fold), Tfam (1.5‐fold), SIRT1 (1.5‐fold), Atrogin 1 (2‐fold), and MuRF1 (5‐fold) gene expression at 3 h post‐exercise. Exhaustive exercise suppressed p70S6K activity to comparable levels immediately post‐exercise (≈20 fmol min−1 mg−1). Despite elevated leucine availability post‐exercise, p70S6K activity remained suppressed (P < 0.05) 3 h post‐exercise in LOW + LEU (28 ± 14 fmol min−1 mg−1), whereas muscle glycogen resynthesis (40 mmol kg−1 dw h−1) was associated with elevated (P < 0.05) p70S6K activity in HIGH (53 ± 30 fmol min−1 mg−1). We conclude: (1) CHO restriction before and during exercise induces “work‐efficient” mitochondrial‐related cell signaling but; (2) post‐exercise CHO and energy restriction maintains p70S6K activity at basal levels despite feeding leucine‐enriched protein. Our data support the practical concept of “fuelling for the work required” as a potential strategy for which to amalgamate train‐low paradigms into periodized training programs.

Mechanistic target of rapamycin (mTOR) resides as two complexes within skeletal muscle. mTOR complex 1 [mTORC1-regulatory associated protein of mTOR (Raptor) positive] regulates skeletal muscle growth, whereas mTORC2 [rapamycin-insensitive companion of mTOR (Rictor) positive] regulates insulin sensitivity. To examine the regulation of these complexes in human skeletal muscle, we utilized immunohistochemical analysis to study the localization of mTOR complexes before and following protein-carbohydrate feeding (FED) and resistance exercise plus protein-carbohydrate feeding (EXFED) in a unilateral exercise model. In basal samples, mTOR and the lysosomal marker lysosomal associated membrane protein 2 (LAMP2) were highly colocalized and remained so throughout. In the FED and EXFED states, mTOR/LAMP2 complexes were redistributed to the cell periphery [wheat germ agglutinin (WGA)-positive staining] (time effect; = 0.025), with 39% (FED) and 26% (EXFED) increases in mTOR/WGA association observed 1 h post-feeding/exercise. mTOR/WGA colocalization continued to increase in EXFED at 3 h (48% above baseline) whereas colocalization decreased in FED (21% above baseline). A significant effect of condition ( = 0.05) was noted suggesting mTOR/WGA colocalization was greater during EXFED. This pattern was replicated in Raptor/WGA association, where a significant difference between EXFED and FED was noted at 3 h post-exercise/feeding ( = 0.014). Rictor/WGA colocalization remained unaltered throughout the trial. Alterations in mTORC1 cellular location coincided with elevated S6K1 kinase activity, which rose to a greater extent in EXFED compared with FED at 1 h post-exercise/feeding ( < 0.001), and only remained elevated in EXFED at the 3 h time point ( = 0.037). Collectively these data suggest that mTORC1 redistribution within the cell is a fundamental response to resistance exercise and feeding, whereas mTORC2 is predominantly situated at the sarcolemma and does not alter localization.

Precise modulation of hepatic glucose metabolism is crucial during the fasting and feeding cycle and is controlled by the actions of circulating insulin and glucagon. The insulin-signaling pathway requires insulin receptor substrate 1 (IRS1) and IRS2, which are found to be dysregulated in diabetes and obesity. The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1A) is a fasting-induced transcriptional coactivator. In nonalcoholic fatty liver disease and in patients with type 2 diabetes, low hepatic PGC1A levels are associated with insulin resistance. However, how PGC1A activity impacts the hepatic insulin-signaling pathway is still unclear. We used gain- and loss-of-function models in mouse primary hepatocytes and measured hepatocyte insulin response by gene and protein expression and ex vivo glucose production. We found that the PGC1A level determines the relative ratio of IRS1 and IRS2 in hepatocytes, impacting insulin receptor signaling via protein kinase B/AKT (AKT). PGC1A drove the expression of IRS2 downstream of glucagon signaling while simultaneously reducing IRS1 expression. We illustrate that glucagon- or PGC1A-induced IRS2 expression was dependent on cAMP Response Element Binding Protein activity and that this was essential for suppression of hepatocyte gluconeogenesis in response to insulin in vitro. We also show that increased hepatic PGC1A improves glucose homeostasis in vivo, revealing a counterregulatory role for PGC1A in repressing uncontrolled glucose production in response to insulin signaling. These data highlight a mechanism by which PGC1A plays dual roles in the control of gluconeogenesis during the fasting-to-fed transition through regulated balance between IRS1 and IRS2 expression.

Key pointsr Previous studies have shown that endurance exercise increases myofibrillar (MyoPS) and mitochondrial (MitoPS) protein synthesis in skeletal muscle.r The mechanistic target of rapamycin (mTOR) is considered to be a key intracellular nutrient-sensing protein complex, which activates MyoPS in response to anabolic stimuli.r Little is known regarding the regulation of MyoPS and MitoPS in response to endurance exercise.r In the present study, we show that MyoPS and MitoPS increase in skeletal muscle following endurance exercise, despite suppression of mTORC1 during the post-exercise recovery period.r Our data suggests that mTORC1 independent processes regulate both MyoPS and MitoPS following acute endurance exercise. AbstractThe present study aimed to investigate the role of the mechanistic target of rapamycin complex 1 (mTORC1) in the regulation of myofibrillar (MyoPS) and mitochondrial (MitoPS) protein synthesis following endurance exercise. Forty-two female C57BL/6 mice performed 1 h of treadmill running (18 m min −1 ; 5°grade), 1 h after I.P. administration of rapamycin (1.5 mg · kg −1 ) or vehicle. To quantify skeletal muscle protein fractional synthesis rates, a flooding dose (50 mg · kg −1 ) of L-[ring-13 C 6 ]phenylalanine was administered via I.P. injection. Blood and gastrocnemius muscle were collected in non-exercised control mice, as well as at 0.5, 3 and 6 h after completing exercise (n = 4 per time point). Skeletal muscle MyoPS and MitoPS were determined by measuring isotope incorporation in their respective protein pools. Activation of the mTORC1-signalling cascade was measured via direct kinase activity assay and immunoblotting, whereas genes related to mitochondrial biogenesis were measured via a quantitative RT-PCR. MyoPS increased rapidly in the vehicle group post-exercise and remained elevated for 6 h, whereas this response was transiently blunted (30 min post-exercise) by rapamycin. By contrast, MitoPS was unaffected by rapamycin, and was increased over the entire post-exercise recovery period in both groups (P < 0.05). Despite rapid increases in both MyoPS and MitoPS, mTORC1 activation was suppressed in both groups post-exercise for the entire 6 h recovery period. Peroxisome proliferator activated receptor-γ coactivator-1α, pyruvate dehydrogenase kinase 4 and mitochondrial transcription factor A mRNA increased post-exercise (P < 0.05) * These authors contributed equally to this work. and this response was augmented by rapamycin (P < 0.05). Collectively, these data suggest that endurance exercise stimulates MyoPS and MitoPS in skeletal muscle independently of mTORC1 activation.

Postexercise high-fat feeding does not augment the mRNA expression of genes associated with regulatory roles in mitochondrial biogenesis, although it does increase lipid gene expression. However, postexercise ribosomal protein S6 kinase 1 activity is reduced under conditions of high-fat feeding, thus potentially impairing skeletal muscle remodeling processes.