Preservation of Liver Protein Synthesis during Dietary Leucine Deprivation Occurs at the Expense of Skeletal Muscle Mass in Mice Deleted for eIF2 Kinase GCN2

The influence of cancer cachexia and chemotherapy and subsequent recovery of skeletal muscle protein mass and turnover was investigated in mice. Cancer cachexia was induced using colon 26 adenocarcinoma, which is characteristic of the human condition, and can be cured with 100% efficacy using an experimental nitrosourea, cystemustine (C6H12CIN3O4S). Reduced food intake was not a factor in these studies. Three days after cachexia began, healthy and tumor-bearing mice were given a single intraperitoneal injection of cystemustine (20 mg/kg). Skeletal muscle mass in tumor-bearing mice was 41% lower ( P < 0.05) than in healthy mice 2 wk after cachexia began. Skeletal muscle wasting was mediated initially by decreased protein synthesis (−38%; P < 0.05) and increased degradation (+131%; P < 0.05); later wasting resulted solely from decreased synthesis (∼−54 to −69%; P < 0.05). Acute cytotoxicity of chemotherapy did not appear to have an important effect on skeletal muscle protein metabolism in either healthy or tumor-bearing mice. Recovery began 2 days after treatment; skeletal muscle mass was only 11% lower than in healthy mice 11 days after chemotherapy. Recovery of skeletal muscle mass was affected initially by decreased protein degradation (−80%; P < 0.05) and later by increased protein synthesis (+46 to +73%; P < 0.05) in cured compared with healthy mice. This study showed that skeletal muscle wasted from cancer cachexia and after chemotherapeutic treatment is able to generate a strong anabolic response by making powerful changes to protein synthesis and degradation.

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Aging, exercise, and muscle protein metabolism

Journal of Applied Physiology ◽

10.1152/japplphysiol.91551.2008 ◽

2009 ◽

Vol 106 (6) ◽

pp. 2040-2048 ◽

Cited By ~ 197

Author(s):

René Koopman ◽

Luc J. C. van Loon

Keyword(s):

Physical Activity ◽

Skeletal Muscle ◽

Protein Synthesis ◽

Food Intake ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

The Elderly ◽

Age Related

Aging is accompanied by a progressive loss of skeletal muscle mass and strength, leading to the loss of functional capacity and an increased risk of developing chronic metabolic disease. The age-related loss of skeletal muscle mass is attributed to a disruption in the regulation of skeletal muscle protein turnover, resulting in an imbalance between muscle protein synthesis and degradation. As basal (fasting) muscle protein synthesis rates do not seem to differ substantially between the young and elderly, many research groups have started to focus on the muscle protein synthetic response to the main anabolic stimuli, i.e., food intake and physical activity. Recent studies suggest that the muscle protein synthetic response to food intake is blunted in the elderly. The latter is now believed to represent a key factor responsible for the age-related decline in skeletal muscle mass. Physical activity and/or exercise stimulate postexercise muscle protein accretion in both the young and elderly. However, the latter largely depends on the timed administration of amino acids and/or protein before, during, and/or after exercise. Prolonged resistance type exercise training represents an effective therapeutic strategy to augment skeletal muscle mass and improve functional performance in the elderly. The latter shows that the ability of the muscle protein synthetic machinery to respond to anabolic stimuli is preserved up to very old age. Research is warranted to elucidate the interaction between nutrition, exercise, and the skeletal muscle adaptive response. The latter is needed to define more effective strategies that will maximize the therapeutic benefits of lifestyle intervention in the elderly.

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REDD1 deletion prevents dexamethasone-induced skeletal muscle atrophy

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00234.2014 ◽

2014 ◽

Vol 307 (11) ◽

pp. E983-E993 ◽

Cited By ~ 49

Author(s):

Florian A. Britto ◽

Gwenaelle Begue ◽

Bernadette Rossano ◽

Aurélie Docquier ◽

Barbara Vernus ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Muscle Mass ◽

Tibialis Anterior ◽

Skeletal Muscle Mass ◽

Gastrocnemius Muscle ◽

Mtorc1 Signaling ◽

Inhibition Of Protein Synthesis ◽

Stress Dependent

REDD1 (regulated in development and DNA damage response 1) has been proposed to inhibit the mechanistic target of rapamycin complex 1 (mTORC1) during in vitro hypoxia. REDD1 expression is low under basal conditions but is highly increased in response to several catabolic stresses, like hypoxia and glucocorticoids. However, REDD1 function seems to be tissue and stress dependent, and its role in skeletal muscle in vivo has been poorly characterized. Here, we investigated the effect of REDD1 deletion on skeletal muscle mass, protein synthesis, proteolysis, and mTORC1 signaling pathway under basal conditions and after glucocorticoid administration. Whereas skeletal muscle mass and typology were unchanged between wild-type (WT) and REDD1-null mice, oral gavage with dexamethasone (DEX) for 7 days reduced tibialis anterior and gastrocnemius muscle weights as well as tibialis anterior fiber size only in WT. Similarly, REDD1 deletion prevented the inhibition of protein synthesis and mTORC1 activity (assessed by S6, 4E-BP1, and ULK1 phosphorylation) observed in gastrocnemius muscle of WT mice following single DEX administration for 5 h. However, our results suggest that REDD1-mediated inhibition of mTORC1 in skeletal muscle is not related to the modulation of the binding between TSC2 and 14-3-3. In contrast, our data highlight a new mechanism involved in mTORC1 inhibition linking REDD1, Akt, and PRAS40. Altogether, these results demonstrated in vivo that REDD1 is required for glucocorticoid-induced inhibition of protein synthesis via mTORC1 downregulation. Inhibition of REDD1 may thus be a strategy to limit muscle loss in glucocorticoid-mediated atrophy.

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Skeletal Muscle Recovery from Disuse Atrophy: Protein Turnover Signaling and Strategies for Accelerating Muscle Regrowth

International Journal of Molecular Sciences ◽

10.3390/ijms21217940 ◽

2020 ◽

Vol 21 (21) ◽

pp. 7940

Author(s):

Timur M. Mirzoev

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Muscle Mass ◽

Mechanical Loading ◽

Protein Turnover ◽

Skeletal Muscle Mass ◽

Molecular Mechanisms ◽

Muscle Protein ◽

Muscle Recovery ◽

Mechanical Unloading

Skeletal muscle fibers have a unique capacity to adjust their metabolism and phenotype in response to alternations in mechanical loading. Indeed, chronic mechanical loading leads to an increase in skeletal muscle mass, while prolonged mechanical unloading results in a significant decrease in muscle mass (muscle atrophy). The maintenance of skeletal muscle mass is dependent on the balance between rates of muscle protein synthesis and breakdown. While molecular mechanisms regulating protein synthesis during mechanical unloading have been relatively well studied, signaling events implicated in protein turnover during skeletal muscle recovery from unloading are poorly defined. A better understanding of the molecular events that underpin muscle mass recovery following disuse-induced atrophy is of significant importance for both clinical and space medicine. This review focuses on the molecular mechanisms that may be involved in the activation of protein synthesis and subsequent restoration of muscle mass after a period of mechanical unloading. In addition, the efficiency of strategies proposed to improve muscle protein gain during recovery is also discussed.

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Dietary protein and exercise training in ageing

Proceedings of The Nutrition Society ◽

10.1017/s0029665110003927 ◽

2010 ◽

Vol 70 (1) ◽

pp. 104-113 ◽

Cited By ~ 28

Author(s):

René Koopman

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Exercise Training ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Human Subjects ◽

The Elderly ◽

Age Related

Ageing is accompanied by a progressive loss of skeletal muscle mass and strength, leading to the loss of functional capacity and an increased risk for developing chronic metabolic diseases such as diabetes. The age-related loss of skeletal muscle mass results from a chronic disruption in the balance between muscle protein synthesis and degradation. As basal muscle protein synthesis rates are likely not different between healthy young and elderly human subjects, it was proposed that muscles from older adults lack the ability to regulate the protein synthetic response to anabolic stimuli, such as food intake and physical activity. Indeed, the dose–response relationship between myofibrillar protein synthesis and the availability of essential amino acids and/or resistance exercise intensity is shifted down and to the right in elderly human subjects. This so-called ‘anabolic resistance’ represents a key factor responsible for the age-related decline in skeletal muscle mass. Interestingly, long-term resistance exercise training is effective as a therapeutic intervention to augment skeletal muscle mass, and improves functional performance in the elderly. The consumption of different types of proteins, i.e. protein hydrolysates, can have different stimulatory effects on muscle protein synthesis in the elderly, which may be due to their higher rate of digestion and absorption. Current research aims to elucidate the interactions between nutrition, exercise and the skeletal muscle adaptive response that will define more effective strategies to maximise the therapeutic benefits of lifestyle interventions in the elderly.

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Combined in vivo muscle mass, muscle protein synthesis and muscle protein breakdown measurement: a ‘Combined Oral Stable Isotope Assessment of Muscle (COSIAM)’ approach

GeroScience ◽

10.1007/s11357-021-00386-2 ◽

2021 ◽

Author(s):

Jessica Cegielski ◽

Daniel J. Wilkinson ◽

Matthew S. Brook ◽

Catherine Boereboom ◽

Bethan E. Phillips ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Stable Isotope ◽

Muscle Mass ◽

Protein Turnover ◽

Skeletal Muscle Mass ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Protein Breakdown ◽

Muscle Protein Breakdown

AbstractOptimising approaches for measuring skeletal muscle mass and turnover that are widely applicable, minimally invasive and cost effective is crucial in furthering research into sarcopenia and cachexia. Traditional approaches for measurement of muscle protein turnover require infusion of expensive, sterile, isotopically labelled tracers which limits the applicability of these approaches in certain populations (e.g. clinical, frail elderly). To concurrently quantify skeletal muscle mass and muscle protein turnover i.e. muscle protein synthesis (MPS) and muscle protein breakdown (MPB), in elderly human volunteers using stable-isotope labelled tracers i.e. Methyl-[D3]-creatine (D3-Cr), deuterium oxide (D2O), and Methyl-[D3]-3-methylhistidine (D3-3MH), to measure muscle mass, MPS and MPB, respectively. We recruited 10 older males (71 ± 4 y, BMI: 25 ± 4 kg.m2, mean ± SD) into a 4-day study, with DXA and consumption of D2O and D3-Cr tracers on day 1. D3-3MH was consumed on day 3, 24 h prior to returning to the lab. From urine, saliva and blood samples, and a single muscle biopsy (vastus lateralis), we determined muscle mass, MPS and MPB. D3-Cr derived muscle mass was positively correlated to appendicular fat-free mass (AFFM) estimated by DXA (r = 0.69, P = 0.027). Rates of cumulative myofibrillar MPS over 3 days were 0.072%/h (95% CI, 0.064 to 0.081%/h). Whole-body MPB over 6 h was 0.052 (95% CI, 0.038 to 0.067). These rates were similar to previous literature. We demonstrate the potential for D3-Cr to be used alongside D2O and D3-3MH for concurrent measurement of muscle mass, MPS, and MPB using a minimally invasive design, applicable for clinical and frail populations.

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The Maintenance of Muscle Mass Is Independent of Testosterone in Adult Male Mice

10.1101/2020.09.24.311266 ◽

2020 ◽

Author(s):

Arik Davidyan ◽

Keith Baar ◽

Sue C. Bodine

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Muscle Mass ◽

Tibialis Anterior ◽

Skeletal Muscle Mass ◽

Tibialis Anterior Muscle ◽

Male Mice ◽

Cross Sectional ◽

Western Blots ◽

Physiological Serum

AbstractTestosterone is considered a potent anabolic agent in skeletal muscle with a well-established role in adolescent growth and development in males. However, alterations in the role of testosterone in the regulation of skeletal muscle mass and function throughout the lifespan has yet to be established. While some studies suggest that testosterone is important for the maintenance of skeletal muscle mass, an understanding of the role this hormone plays in young, adult, and old males with normal and low serum testosterone levels is lacking. We investigated the role testosterone plays in the maintenance of muscle mass by examining the effect of orchiectomy-induced testosterone depletion in C57Bl6 male mice at ages ranging from early postnatal through old age; the age groups we used included 1.5-, 5-, 12-, and 24-month old mice. Following 28 days of testosterone depletion, we assessed mass and fiber cross-sectional-area (CSA) of the tibialis anterior, gastrocnemius, and quadriceps muscles. In addition, we measured global rates of protein synthesis and degradation using the SuNSET method, western blots, and enzyme activity assays. 28 days of testosterone depletion resulted in smaller muscle mass in the two youngest cohorts but had no effect in the two older ones. Mean CSA decreased only in the youngest cohort and only in the tibialis anterior muscle. Testosterone depletion resulted in a general increase in proteasome activity at all ages. We did not detect changes in protein synthesis at the terminal time point. This data suggest that within physiological serum concentrations, testosterone is not important for the maintenance of muscle mass in mature male mice; however, in young mice testosterone is crucial for normal growth.

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Maintenance of muscle mass in adult male mice is independent of testosterone

PLoS ONE ◽

10.1371/journal.pone.0240278 ◽

2021 ◽

Vol 16 (3) ◽

pp. e0240278

Author(s):

Arik Davidyan ◽

Suraj Pathak ◽

Keith Baar ◽

Sue C. Bodine

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Muscle Mass ◽

Tibialis Anterior ◽

Skeletal Muscle Mass ◽

Tibialis Anterior Muscle ◽

Male Mice ◽

Cross Sectional ◽

Western Blots ◽

Physiological Serum

Testosterone is considered a potent anabolic agent in skeletal muscle with a well-established role in adolescent growth and development in males. However, the role of testosterone in the regulation of skeletal muscle mass and function throughout the lifespan has yet to be fully established. While some studies suggest that testosterone is important for the maintenance of skeletal muscle mass, an understanding of the role this hormone plays in young, adult, and old males with normal and low serum testosterone levels is lacking. We investigated the role testosterone plays in the maintenance of muscle mass by examining the effect of orchiectomy-induced testosterone depletion in C57Bl6 male mice at ages ranging from early postnatal through old age (1.5-, 5-, 12-, and 24-month old mice). Following 28 days of testosterone depletion, we assessed mass and fiber cross-sectional-area (CSA) of the tibialis anterior, gastrocnemius, and quadriceps muscles. In addition, we measured global rates of protein synthesis and degradation using the SuNSET method, western blots, and enzyme activity assays. Twenty-eight days of testosterone depletion resulted in reduced muscle mass in the two youngest cohorts, but had no effect in the two oldest cohorts. Mean CSA decreased only in the youngest cohort and only in the tibialis anterior muscle. Testosterone depletion resulted in a general increase in proteasome activity at all ages. No change in protein synthesis was detected at the terminal time point. These data suggest that within physiological serum concentrations, testosterone may not be critical for the maintenance of muscle mass in mature male mice; however, in young mice testosterone is crucial for normal growth.

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Mechanotransduction and the regulation of protein synthesis in skeletal muscle

Proceedings of The Nutrition Society ◽

10.1079/pns2004357 ◽

2004 ◽

Vol 63 (2) ◽

pp. 331-335 ◽

Cited By ~ 50

Author(s):

T. A. Hornberger ◽

K. A. Esser

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Resistance Exercise ◽

Muscle Mass ◽

High Resistance ◽

Growth Process ◽

Skeletal Muscle Mass ◽

Cell Type

Repeated bouts of resistance exercise produce an increase in skeletal muscle mass. The accumulation of protein associated with the growth process results from a net increase in protein synthesis relative to breakdown. While the effect of resistance exercise on muscle mass has long been recognized, the mechanisms underlying the link between high-resistance contractions and the regulation of protein synthesis and breakdown are, to date, poorly understood. In the present paper skeletal muscle will be viewed as a mechanosensitive cell type and the possible mechanisms through which mechanically-induced signalling events lead to changes in rates of protein synthesis will be examined.

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