Changing demographics make it ever more important to understand the modifiable risk factors for disability and loss of independence with advancing age. For more than two decades there has been increasing interest in the role of sarcopenia, the age-related loss of muscle or lean mass, in curtailing active and healthy aging. There is now evidence to suggest that lack of strength, or dynapenia, is a more constant factor in compromised wellbeing in old age and it is apparent that the decline in muscle mass and the decline in strength can take quite different trajectories. This demands recognition of the concept of muscle quality; that is the force generating per capacity per unit cross-sectional area (CSA). An understanding of the impact of aging on skeletal muscle will require attention to both the changes in muscle size and the changes in muscle quality. The aim of this review is to present current knowledge of the decline in human muscle mass and strength with advancing age and the associated risk to health and survival and to review the underlying changes in muscle characteristics and the etiology of sarcopenia. Cross-sectional studies comparing young (18–45 years) and old (>65 years) samples show dramatic variation based on the technique used and population studied. The median of values of rate of loss reported across studies is 0.47% per year in men and 0.37% per year in women. Longitudinal studies show that in people aged 75 years, muscle mass is lost at a rate of 0.64–0.70% per year in women and 0.80–00.98% per year in men. Strength is lost more rapidly. Longitudinal studies show that at age 75 years, strength is lost at a rate of 3–4% per year in men and 2.5–3% per year in women. Studies that assessed changes in mass and strength in the same sample report a loss of strength 2–5 times faster than loss of mass. Loss of strength is a more consistent risk for disability and death than is loss of muscle mass.

Aim We investigated architectural, functional and molecular responses of human skeletal muscle to concentric (CON) or eccentric (ECC) resistance training (RT). Methods Twelve young males performed 10 weeks of concentric (CON) or eccentric (ECC) resistance training (RT) (n = 6 CON, 6 ECC). An additional 14 males were recruited to evaluate acute muscle fascicle behaviour and molecular signalling in biopsies collected from vastus lateralis (VL) after 30 min of single bouts of CON or ECC exercise. VL volume was measured by magnetic resonance imaging. Muscle architecture (fascicle length, Lf; pennation angle, PA) was evaluated by ultrasonography. Muscle remodelling signals to CON or ECC loading [MAPK/AKT‐mammalian target of rapamycin (mTOR) signalling] and inflammatory pathway (TNFαMurf‐1‐MAFbx) were evaluated by immunoblotting. Results Despite the ~1.2‐fold greater load of the ECC group, similar increases in muscle volume (+8% CON and +6% ECC) and in maximal voluntary isometric contraction (+9% CON and +11% ECC) were found after RT. However, increases in Lf were greater after ECC than CON (+12 vs. +5%) while increases in PA were greater in CON than ECC (+30 vs. +5%). Distinct architectural adaptations were associated with preferential growth in the distal regions of VL for ECC (+ECC +8% vs. +CON +2) and mid belly for CON (ECC +7 vs. CON +11%). While MAPK activation (p38MAPK, ERK1/2, p90RSK) was specific to ECC, neither mode affected AKT‐mTOR or inflammatory signalling 30 min after exercise. Conclusion Muscle growth with CON and ECC RT occurs with different morphological adaptations reflecting distinct fibre fascicle behaviour and molecular responses.

Quantification of muscle protein synthesis (MPS) remains a cornerstone for understanding the control of muscle mass. Traditional [(13)C]amino acid tracer methodologies necessitate sustained bed rest and intravenous cannulation(s), restricting studies to ~12 h, and thus cannot holistically inform on diurnal MPS. This limits insight into the regulation of habitual muscle metabolism in health, aging, and disease while querying the utility of tracer techniques to predict the long-term efficacy of anabolic/anticatabolic interventions. We tested the efficacy of the D2O tracer for quantifying MPS over a period not feasible with (13)C tracers and too short to quantify changes in mass. Eight men (22 ± 3.5 yr) undertook one-legged resistance exercise over an 8-day period (4 × 8-10 repetitions, 80% 1RM every 2nd day, to yield "nonexercised" vs. "exercise" leg comparisons), with vastus lateralis biopsies taken bilaterally at 0, 2, 4, and 8 days. After day 0 biopsies, participants consumed a D2O bolus (150 ml, 70 atom%); saliva was collected daily. Fractional synthetic rates (FSRs) of myofibrillar (MyoPS), sarcoplasmic (SPS), and collagen (CPS) protein fractions were measured by GC-pyrolysis-IRMS and TC/EA-IRMS. Body water initially enriched at 0.16-0.24 APE decayed at ~0.009%/day. In the nonexercised leg, MyoPS was 1.45 ± 0.10, 1.47 ± 0.06, and 1.35 ± 0.07%/day at 0-2, 0-4, and 0-8 days, respectively (~0.05-0.06%/h). MyoPS was greater in the exercised leg (0-2 days: 1.97 ± 0.13%/day; 0-4 days: 1.96 ± 0.15%/day, P < 0.01; 0-8 days: 1.79 ± 0.12%/day, P < 0.05). CPS was slower than MyoPS but followed a similar pattern, with the exercised leg tending to yield greater FSRs (0-2 days: 1.14 ± 0.13 vs. 1.45 ± 0.15%/day; 0-4 days: 1.13 ± 0.07%/day vs. 1.47 ± 0.18%/day; 0-8 days: 1.03 ± 0.09%/day vs. 1.40 ± 0.11%/day). SPS remained unchanged. Therefore, D2O has unrivaled utility to quantify day-to-day MPS in humans and inform on short-term changes in anabolism and presumably catabolism alike.

Key points Resistance exercise training (RET) is one of the most effective strategies for preventing declines in skeletal muscle mass and strength with age.Hypertrophic responses to RET with age are diminished compared to younger individuals.In response to 6 weeks RET, we found blunted hypertrophic responses with age are underpinned by chronic deficits in long‐term muscle protein synthesis.We show this is likely to be the result of multifactorial deficits in anabolic hormones and blunted translational efficiency and capacity.These results provide great insight into age‐related exercise adaptations and provide a platform on which to devise appropriate nutritional and exercise interventions on a longer term basis. AbstractAgeing is associated with impaired hypertrophic responses to resistance exercise training (RET). Here we investigated the aetiology of ‘anabolic resistance’ in older humans. Twenty healthy male individuals, 10 younger (Y; 23 ± 1 years) and 10 older (O; 69 ± 3 years), performed 6 weeks unilateral RET (6 × 8 repetitions, 75% of one repetition maximum (1‐RM), 3 times per week). After baseline bilateral vastus lateralis (VL) muscle biopsies, subjects consumed 150 ml D2O (70 atom%; thereafter 50 ml week−1), further bilateral VL muscle biopsies were taken at 3 and 6 weeks to quantify muscle protein synthesis (MPS) via gas chromatography–pyrolysis–isotope ratio mass spectrometry. After RET, 1‐RM increased in Y (+35 ± 4%) and O (+25 ± 3%; P < 0.01), while MVC increased in Y (+21 ± 5%; P < 0.01) but not O (+6 ± 3%; not significant (NS)). In comparison to Y, O displayed blunted RET‐induced increases in muscle thickness (at 3 and 6 weeks, respectively, Y: +8 ± 1% and +11 ± 2%, P < 0.01; O: +2.6 ± 1% and +3.5 ± 2%, NS). While ‘basal’ longer term MPS was identical between Y and O (∼1.35 ± 0.1% day−1), MPS increased in response to RET only in Y (3 weeks, Y: 1.61 ± 0.1% day−1; O: 1.49 ± 0.1% day−1). Consistent with this, O exhibited inferior ribosomal biogenesis (RNA:DNA ratio and c‐MYC induction: Y: +4 ± 2 fold change; O: +1.9 ± 1 fold change), translational efficiency (S6K1 phosphorylation, Y: +10 ± 4 fold change; O: +4 ± 2 fold change) and anabolic hormone milieu (testosterone, Y: 367 ± 19; O: 274 ± 19 ng dl−1 (all P < 0.05). Anabolic resistance is thus multifactorial.

Resistance exercise training (RET) is widely used to increase muscle mass in athletes and also aged/cachectic populations. However, the time course and metabolic and molecular control of hypertrophy remain poorly defined. Using newly developed deuterium oxide (D2O)-tracer techniques, we investigated the relationship between long-term muscle protein synthesis (MPS) and hypertrophic responses to RET. A total of 10 men (23 ± 1 yr) undertook 6 wk of unilateral (1-legged) RET [6 × 8 repetitions, 75% 1 repetition maximum (1-RM) 3/wk], rendering 1 leg untrained (UT) and the contralateral, trained (T). After baseline bilateral vastus lateralis (VL) muscle biopsies, subjects consumed 150 ml D2O (70 atom percentage; thereafter 50 ml/wk) with regular body water monitoring in saliva via high-temperature conversion elemental analyzer:isotope ratio mass spectrometer. Further bilateral VL muscle biopsies were taken at 3 and 6 wk to temporally quantify MPS via gas chromatography:pyrolysis:isotope ratio mass spectrometer. Expectedly, only the T leg exhibited marked increases in function [i.e., 1-RM/maximal voluntary contraction (60°)] and VL thickness (peaking at 3 wk). Critically, whereas MPS remained unchanged in the UT leg (e.g., ∼1.35 ± 0.08%/d), the T leg exhibited increased MPS at 0-3 wk (1.6 ± 0.01%/d), but not at 3-6 wk (1.29 ± 0.11%/d); this was reflected by dampened acute mechanistic target of rapamycin complex 1 signaling responses to RET, beyond 3 wk. Therefore, hypertrophic remodeling is most active during the early stages of RET, reflecting longer-term MPS. Moreover, D2O heralds promise for coupling MPS and muscle mass and providing insight into the control of hypertrophy and efficacy of anabolic interventions.

PJ. Intake of low-dose leucine-rich essential amino acids stimulates muscle anabolism equivalently to bolus whey protein in older women at rest and after exercise. Am J Physiol Endocrinol Metab 308: E1056-E1065, 2015. First published March 31, 2015; doi:10.1152/ajpendo.00481.2014.-Dysregulated anabolic responses to nutrition/exercise may contribute to sarcopenia; however, these characteristics are poorly defined in female populations. We determined the effects of two feeding regimes in older women (66 Ϯ 2.5 yr; n ϭ 8/group): bolus whey protein (WP-20 g) or novel low-dose leucine-enriched essential amino acids (EAA) [LEAA; 3 g (40% leucine)]. Using [ 13 C6]phenylalanine infusions, we quantified muscle (MPS) and albumin (APS) protein synthesis at baseline and in response to both feeding (FED) and feeding plus exercise (FED-EX; 6 ϫ 8 knee extensions at 75% 1-repetition maximum). We also quantified plasma insulin/AA concentrations, whole leg (LBF)/muscle microvascular blood flow (MBF), and muscle anabolic signaling by phosphoimmunoblotting. Plasma insulinemia and EAA/aemia were markedly greater after WP than LEAA (P Ͻ 0.001). Neither LEAA nor WP modified LBF in response to FED or FED-EX, whereas MBF increased to a similar extent in both groups only after FED-EX (P Ͻ 0.05). In response to FED, both WP and LEAA equally stimulated MPS 0 -2 h (P Ͻ 0.05), abating thereafter (0 -4 h, P Ͼ 0.05). In contrast, after FED-EX, MPS increased at 0 -2 h and remained elevated at 0 -4 h (P Ͻ 0.05) with both WP and LEAA. No anabolic signals quantifiably increased after FED, but p70 S6K1 Thr 389 increased after FED-EX (2 h, P Ͻ 0.05). APS increased similarly after WP and LEAA. Older women remain subtly responsive to nutrition Ϯ exercise. Intriguingly though, bolus WP offers no trophic advantage over LEAA. skeletal muscle; blood flow; protein synthesis; aging; amino acids; exercise ILL HEALTH ASSOCIATED WITH AGING represents a major socioeconomic burden, especially given shifting demographics toward a more aged, populous world. In particular, the loss of skeletal muscle mass associated with aging, or sarcopenia, is a major clinical issue. For instance, not only are there established links between low muscle mass and all-cause mortality per se (1), but also, lower skeletal muscle mass associated with sarcopenia leads to increased frailty, risk of falls, sedentarism, poor quality of life, and prevalence of metabolic comorbidities (17, 53).The two major extrinsic influences over muscle mass are nutrition and physical activity. For example, oral intake of protein-based foods containing essential amino acids (EAA) leads to a transient (2-3 h; see Ref.2) stimulation of muscle protein synthesis (MPS) in younger men. This brief increase in MPS above postabsorptive rates serves the purpose of replenishing protein stores lost during fasting, ensuring preservation of muscle protein mass. Similarly, physical activity is a prerequisite for maintenance of a healthy muscle mass. For example, inactivity (6, 20) causes muscle atrophy by inducing "anabo...

We recently reported that the greatest distinguishing feature between eccentric (ECC) and concentric (CON) muscle loading lays in architectural adaptations: ECC favors increases in fascicle length (Lf), associated with distal vastus lateralis muscle (VL) hypertrophy, and CON increases in pennation angle (PA). Here, we explored the interactions between structural and morphological remodeling, assessed by ultrasound and dual x-ray absorptiometry (DXA), and long-term muscle protein synthesis (MPS), evaluated by deuterium oxide (D2O) tracing technique. Ten young males (23 ± 4 years) performed unilateral resistance exercise training (RET) three times/week for 4 weeks; thus, one-leg trained concentrically while the contralateral performed ECC exercise only at 80% of either CON or ECC one repetition maximum (1RM). Subjects consumed an initial bolus of D2O (150 mL), while a 25-mL dose was thereafter provided every 8 days. Muscle biopsies from VL midbelly (MID) and distal myotendinous junction (MTJ) were collected at 0 and 4-weeks. MPS was then quantified via GC–pyrolysis–IRMS over the 4-week training period. Expectedly, ECC and CON RET resulted in similar increases in VL muscle thickness (MT) (7.5% vs. 8.4%, respectively) and thigh lean mass (DXA) (2.3% vs. 3%, respectively), albeit through distinct remodeling: Lf increasing more after ECC (5%) versus CON (2%) and PA increasing after CON (7% vs. 3%). MPS did not differ between contractile modes or biopsy sites (MID-ECC: 1.42 vs. MID-CON: 1.4% day−1; MTJ-ECC: 1.38 vs. MTJ-CON: 1.39% day−1). Muscle thickness at MID site increased similarly following ECC and CON RET, reflecting a tendency for a contractile mode-independent correlation between MPS and MT (P = 0.07; R2 = 0.18). We conclude that, unlike MT, distinct structural remodeling responses to ECC or CON are not reflected in MPS; the molecular mechanisms of distinct protein deposition, and/or the role of protein breakdown in mediating these responses remain to be defined.

Compromised limb blood flow in aging may contribute to the development of sarcopenia, frailty, and the metabolic syndrome. We developed a novel contrast-enhanced ultrasound technique using Sonovue™ to characterize muscle microvasculature responses to an oral feeding stimulus (15 g essential amino acids) in young (∼20 years) and older (∼70 years) men. Intensity-time replenishment curves were made via an ultrasound probe “fixed” over the quadriceps, with intermittent high mechanical index destruction of microbubbles within muscle vasculature. This permitted real-time measures of microvascular blood volume (MBV), microvascular flow velocity (MFV) and their product, microvascular blood flow (MBF). Leg blood flow (LBF) was measured by Doppler and insulin by enzyme-linked immunosorbent assay. Steady-state contrast concentrations needed for comparison between different physiological states were achieved <150 sec from commencing Sonovue™ infusion, and MFV and MBV measurements were completed <120 sec thereafter. Interindividual coefficients of variation in MBV and MFV were 35–40%, (N = 36). Younger men (N = 6) exhibited biphasic vascular responses to feeding with early increases in MBV (+36%, P < 0.008 45 min post feed) reflecting capillary recruitment, and late increases in MFV (+77%, P < 0.008) and MBF (+130%, P < 0.007 195 min post feed) reflecting more proximal vessel dilatation. Early MBV responses were synchronized with peak insulin but not increased LBF, while later changes in MFV and MBF occurred with insulin at post absorptive values but alongside increased LBF. All circulatory responses were absent in old men (N = 7). Thus, impaired postprandial circulation could impact age-related declines in muscle glucose disposal, protein anabolism, and muscle mass.