Benjamin T. Wall

Skeletal muscle atrophy during short-term disuse: Implications for age-related sarcopenia

Situations such as the recovery from injury and illness can lead to enforced periods of muscle disuse or unloading. Such circumstances lead to rapid skeletal muscle atrophy, loss of functional strength and a multitude of related negative health consequences. The elderly population is particularly vulnerable to the acute challenges of muscle disuse atrophy. Any loss of skeletal muscle mass must be underpinned by a chronic imbalance between muscle protein synthesis and breakdown rates. It is recognized that muscle atrophy during prolonged (>10 days) disuse is brought about primarily by declines in post-absorptive and post-prandial muscle protein synthesis rates, without a clear contribution from changes in muscle protein breakdown. Few data are available on the impact of short-term disuse (<10 days) on muscle protein turnover in humans. However, indirect evidence indicates that considerable muscle atrophy occurs during this early phase, and is likely attributed to a rapid increase in muscle protein breakdown accompanied by the characteristic decline in muscle protein synthesis. Short-term disuse atrophy is of particular relevance in the development of sarcopenia, as it has been suggested that successive short periods of muscle disuse, due to sickness or injury, accumulate throughout an individuals lifespan and contributes considerably to the net muscle loss observed with aging. Research is warranted to elucidate the physiological and molecular basis for rapid muscle loss during short periods of disuse. Such mechanistic insight will allow the characterization of nutritional, exercise and/or pharmacological interventions to prevent or attenuate muscle loss during periods of disuse and therefore aid in the treatment of age-related sarcopenia.

Leucine co-ingestion improves post-prandial muscle protein accretion in elderly men

BACKGROUND & AIMS It has been speculated that the amount of leucine in a meal largely determines the post-prandial muscle protein synthetic response to food intake. The present study investigates the impact of leucine co-ingestion on subsequent post-prandial muscle protein accretion following the ingestion of a single bolus of dietary protein in elderly males. METHODS Twenty-four elderly men (74.3±1.0 y) were randomly assigned to ingest 20 g intrinsically L-[1-(13)C]phenylalanine-labeled casein protein with (PRO+LEU) or without (PRO) 2.5 g crystalline leucine. Ingestion of specifically produced intrinsically labeled protein allowed us to create a plasma phenylalanine enrichment pattern similar to the absorption pattern of phenylalanine from the ingested protein and assess the subsequent post-prandial incorporation of L-[1-(13)C] phenylalanine into muscle protein. RESULTS Plasma amino acid concentrations increased rapidly following protein ingestion in both groups, with higher leucine concentrations observed in the PRO+LEU compared with the PRO group (P<0.01). Plasma L-[1-(13)C]phenylalanine enrichments increased rapidly and to a similar extent in both groups following protein ingestion. Muscle protein-bound L-[1-(13)C]phenylalanine enrichments were significantly greater after PRO+LEU when compared with PRO at 2 h (72%; 0.0078±0.0010 vs. 0.0046±0.00100 MPE, respectively; P<0.05) and 6 h (25%; 0.0232±0.0015 vs. 0.0185±0.0010 MPE, respectively; P<0.05) following protein ingestion. The latter translated into a greater muscle protein synthetic rate following PRO+LEU compared with PRO over the entire 6 h post-prandial period (22%; 0.049±0.003 vs. 0.040±0.003% h(-1), respectively; P<0.05). CONCLUSION Leucine co-ingestion with a bolus of pure dietary protein further stimulates post-prandial muscle protein synthesis rates in elderly men.

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.

Nutritional strategies to attenuate muscle disuse atrophy

Situations such as recovery from injury or illness require otherwise healthy humans to undergo periods of disuse, which lead to considerable losses of skeletal muscle mass and, subsequently, numerous negative health consequences. It has been established that prolonged disuse (>10 days) leads to a decline in basal and postprandial rates of muscle protein synthesis, without an apparent change in muscle protein breakdown. It also seems, however, that an early and transient (1-5 days) increase in basal muscle protein breakdown may also contribute to disuse atrophy. A period of disuse reduces energy requirements and appetite. Consequently, food intake generally declines, resulting in an inadequate dietary protein consumption to allow proper muscle mass maintenance. Evidence suggests that maintaining protein intake during a period of disuse attenuates disuse atrophy. Furthermore, supplementation with dietary protein and/or essential amino acids can be applied to further aid in muscle mass preservation during disuse. Such strategies are of particular relevance to the older patient at risk of developing sarcopenia. More work is required to elucidate the impact of disuse on basal and postprandial rates of muscle protein synthesis and breakdown. Such information will provide novel targets for nutritional interventions to further attenuate muscle disuse atrophy and, as such, support healthy aging.

Substantial skeletal muscle loss occurs during only 5 days of disuse.

The impact of disuse on the loss of skeletal muscle mass and strength has been well documented. Given that most studies have investigated muscle atrophy after more than 2 weeks of disuse, few data are available on the impact of shorter periods of disuse. We assessed the impact of 5 and 14 days of disuse on skeletal muscle mass, strength and associated intramuscular molecular signalling responses.

Aging Is Accompanied by a Blunted Muscle Protein Synthetic Response to Protein Ingestion

Purpose Progressive loss of skeletal muscle mass with aging (sarcopenia) forms a global health concern. It has been suggested that an impaired capacity to increase muscle protein synthesis rates in response to protein intake is a key contributor to sarcopenia. We assessed whether differences in post-absorptive and/or post-prandial muscle protein synthesis rates exist between large cohorts of healthy young and older men. Procedures We performed a cross-sectional, retrospective study comparing in vivo post-absorptive muscle protein synthesis rates determined with stable isotope methodologies between 34 healthy young (22±1 y) and 72 older (75±1 y) men, and post-prandial muscle protein synthesis rates between 35 healthy young (22±1 y) and 40 older (74±1 y) men. Findings Post-absorptive muscle protein synthesis rates did not differ significantly between the young and older group. Post-prandial muscle protein synthesis rates were 16% lower in the older subjects when compared with the young. Muscle protein synthesis rates were >3 fold more responsive to dietary protein ingestion in the young. Irrespective of age, there was a strong negative correlation between post-absorptive muscle protein synthesis rates and the increase in muscle protein synthesis rate following protein ingestion. Conclusions Aging is associated with the development of muscle anabolic inflexibility which represents a key physiological mechanism underpinning sarcopenia.

Neuromuscular electrical stimulation prevents muscle disuse atrophy during leg immobilization in humans

Short periods of muscle disuse, due to illness or injury, result in substantial skeletal muscle atrophy. Recently, we have shown that a single session of neuromuscular electrical stimulation (NMES) increases muscle protein synthesis rates. The aim was to investigate the capacity for daily NMES to attenuate muscle atrophy during short‐term muscle disuse.

Disuse Impairs the Muscle Protein Synthetic Response to Protein Ingestion in Healthy Men

BACKGROUND Disuse leads to rapid skeletal muscle atrophy, which brings about numerous negative health consequences. Muscle disuse atrophy is, at least in part, attributed to a decline in basal (postabsorptive) muscle protein synthesis rates. However, it remains to be determined whether muscle disuse also impairs the muscle protein synthetic response to dietary protein ingestion. PURPOSE We assessed muscle protein synthesis rates after protein ingestion before and after a period of disuse in humans. METHODS Twelve healthy young (24 ± 1 year) men underwent a 14-day period of one-legged knee immobilization by way of a full leg cast. Before and after the immobilization period, quadriceps cross-sectional area, muscle strength, skeletal muscle protein synthesis rates, and associated im (intramuscular) molecular signaling were assessed. Continuous infusions of l-[ring-²H₅]phenylalanine were applied to assess mixed-muscle protein fractional synthetic rates after the ingestion of 20 g dietary protein. RESULTS Immobilization led to an 8.4% ± 2.8% (P < .001) and 22.9% ± 2.6% (P < .001) decrease in quadriceps muscle cross-sectional area and strength, respectively. Immobilization resulted in a 31% ± 12% reduction in postprandial muscle protein synthesis rates (from 0.046% ± 0.004% to 0.032% ± 0.006% per hour; P < .05). These findings were observed without any discernible changes in the skeletal muscle phosphorylation status of mammalian target of rapamycin or p70 ribosomal protein S6 kinase. CONCLUSIONS A short period of muscle disuse impairs the muscle protein synthetic response to dietary protein intake in vivo in healthy young men. Thus, anabolic resistance to protein ingestion contributes significantly to the loss of muscle mass that is observed during disuse.

One Week of Bed Rest Leads to Substantial Muscle Atrophy and Induces Whole-Body Insulin Resistance in the Absence of Skeletal Muscle Lipid Accumulation

Short (<10 days) periods of muscle disuse, often necessary for recovery from illness or injury, lead to various negative health consequences. The current study investigated mechanisms underlying disuse-induced insulin resistance, taking into account muscle atrophy. Ten healthy, young males (age: 23 ± 1 years; BMI: 23.0 ± 0.9 kg · m−2) were subjected to 1 week of strict bed rest. Prior to and after bed rest, lean body mass (dual-energy X-ray absorptiometry) and quadriceps cross-sectional area (CSA; computed tomography) were assessed, and peak oxygen uptake (VO2peak) and leg strength were determined. Whole-body insulin sensitivity was measured using a hyperinsulinemic-euglycemic clamp. Additionally, muscle biopsies were collected to assess muscle lipid (fraction) content and various markers of mitochondrial and vascular content. Bed rest resulted in 1.4 ± 0.2 kg lean tissue loss and a 3.2 ± 0.9% decline in quadriceps CSA (both P < 0.01). VO2peak and one-repetition maximum declined by 6.4 ± 2.3 (P < 0.05) and 6.9 ± 1.4% (P < 0.01), respectively. Bed rest induced a 29 ± 5% decrease in whole-body insulin sensitivity (P < 0.01). This was accompanied by a decline in muscle oxidative capacity, without alterations in skeletal muscle lipid content or saturation level, markers of oxidative stress, or capillary density. In conclusion, 1 week of bed rest substantially reduces skeletal muscle mass and lowers whole-body insulin sensitivity, without affecting mechanisms implicated in high-fat diet–induced insulin resistance.

Neuromuscular electrical stimulation increases muscle protein synthesis in elderly type 2 diabetic men

Physical activity is required to attenuate the loss of skeletal muscle mass with aging. Short periods of muscle disuse, due to sickness or hospitalization, reduce muscle protein synthesis rates, resulting in rapid muscle loss. The present study investigates the capacity of neuromuscular electrical stimulation (NMES) to increase in vivo skeletal muscle protein synthesis rates in older type 2 diabetes patients. Six elderly type 2 diabetic men (70 ± 2 yr) were subjected to 60 min of one-legged NMES. Continuous infusions with L-[ring-¹³C₆]phenylalanine were applied, with blood and muscle samples being collected regularly to assess muscle protein synthesis rates in both the stimulated (STIM) and nonstimulated control (CON) leg during 4 h of recovery after NMES. Furthermore, mRNA expression of key genes implicated in the regulation of muscle mass were measured over time in the STIM and CON leg. Muscle protein synthesis rates were greater in the STIM compared with the CON leg during recovery from NMES (0.057 ± 0.008 vs. 0.045 ± 0.008%/h, respectively, P < 0.01). Skeletal muscle myostatin mRNA expression in the STIM leg tended to increase immediately following NMES compared with the CON leg (1.63- vs. 1.00-fold, respectively, P = 0.07) but strongly declined after 2 and 4 h of recovery in the STIM leg only. In conclusion, this is the first study to show that NMES directly stimulates skeletal muscle protein synthesis rates in vivo in humans. NMES likely represents an effective interventional strategy to attenuate muscle loss in elderly individuals during bed rest and/or in other disuse states.