Decline In Muscle Protein Synthesis Research Articles

Can exercise prevent the age‐related decline in adaptive homeostasis? Evidence across organisms and tissues

Can exercise prevent the age‐related decline in adaptive homeostasis? Evidence across organisms and tissues

Effect of High-Protein Diets on Integrated Myofibrillar Protein Synthesis before Anterior Cruciate Ligament Reconstruction: A Randomized Controlled Pilot Study.

Increasing dietary protein intake during periods of muscle disuse may mitigate the resulting decline in muscle protein synthesis (MPS). The purpose of this randomized pilot study was to determine the effect of increased protein intake during periods of disuse before anterior cruciate ligament (ACL) reconstruction on myofibrillar protein synthesis (MyoPS), and proteolytic and myogenic gene expression. Six healthy, young males (30 ± 9 y) were randomized to consume a high-quality, optimal protein diet (OP; 1.9 g·kg−1·d−1) or adequate protein diet (AP; 1.2 g·kg−1·d−1) for two weeks before ACL reconstruction. Muscle biopsies collected during surgery were used to measure integrated MyoPS during the intervention (via daily deuterium oxide ingestion) and gene expression at the time of surgery. MyoPS tended to be higher, with a large effect size in OP compared to AP (0.71 ± 0.1 and 0.54 ± 0.1%·d−1; p = 0.076; g = 1.56). Markers of proteolysis and myogenesis were not different between groups (p > 0.05); however, participants with greater MyoPS exhibited lower levels of MuRF1 gene expression compared to those with lower MyoPS (r = −0.82, p = 0.047). The data from this pilot study reveal a potential stimulatory effect of increased daily protein intake on MyoPS during injury-mediated disuse conditions that warrants further investigation.

Transcriptomic links to muscle mass loss and declines in cumulative muscle protein synthesis during short-term disuse in healthy younger humans.

Muscle disuse leads to a rapid decline in muscle mass, with reduced muscle protein synthesis (MPS) considered the primary physiological mechanism. Here, we employed a systems biology approach to uncover molecular networks and key molecular candidates that quantitatively link to the degree of muscle atrophy and/or extent of decline in MPS during short-term disuse in humans. After consuming a bolus dose of deuterium oxide (D2 O; 3mL.kg-1 ), eight healthy males (22±2years) underwent 4days of unilateral lower-limb immobilization. Bilateral muscle biopsies were obtained post-intervention for RNA sequencing and D2 O-derived measurement of MPS, with thigh lean mass quantified using dual-energy X-ray absorptiometry. Application of weighted gene co-expression network analysis identified 15 distinct gene clusters ("modules") with an expression profile regulated by disuse and/or quantitatively connected to disuse-induced muscle mass or MPS changes. Module scans for candidate targets established an experimentally tractable set of candidate regulatory molecules (242 hub genes, 31 transcriptional regulators) associated with disuse-induced maladaptation, many themselves potently tied to disuse-induced reductions in muscle mass and/or MPS and, therefore, strong physiologically relevant candidates. Notably, we implicate a putative role for muscle protein breakdown-related molecular networks in impairing MPS during short-term disuse, and further establish DEPTOR (a potent mTOR inhibitor) as a critical mechanistic candidate of disuse driven MPS suppression in humans. Overall, these findings offer a strong benchmark for accelerating mechanistic understanding of short-term muscle disuse atrophy that may help expedite development of therapeutic interventions.

Disuse skeletal muscle atrophy in humans. Proteomic and molecular adaptations

Disuse skeletal muscle atrophy in humans. Proteomic and molecular adaptations

CrossTalk proposal: The dominant mechanism causing disuse muscle atrophy is decreased protein synthesis.

CrossTalk proposal: The dominant mechanism causing disuse muscle atrophy is decreased protein synthesis.

Proteomic Profiling and Its Applications to Muscle Aging and Sarcopenia

Proteomic Profiling and Its Applications to Muscle Aging and Sarcopenia

Effects of 10 days of bedrest on body composition and the rate of muscle protein synthesis in older men and women

The effects of bed rest are well described in younger subjects but have not been evaluated in older adults. The objective of this study was to examine the effects of 10 days of bed rest on body composition changes and muscle protein synthesis in healthy older people. Eight subjects (68 ± 5 yo, M/F: 2/6) remained in bed, except for toileting, for 10 consecutive days. All subjects consumed a eucaloric diet providing 0.8 g protein·kg−1·d−1. Body composition (DEXA), and muscle protein synthesis (24-hr infusion of 13C6-phenylalanine) were assessed before and immediately after bed rest. On average, there was a 7% loss of lower extremity lean tissue in these subjects (14454 g to 13511 g, p<0.05), and the fractional muscle protein synthetic rate declined 44% (n=4, 0.086 %·hr−1 to 0.048 %·hr−1, p<0.05). These results indicate that there is a significant loss of muscle, with a more pronounced decline in muscle protein synthesis as a result of 10 days of bed rest. This loss of muscle in these older people after 10 days is greater than that seen in previous studies in young subjects after 28 days of bed rest. These data are of particular significance given the number of older adults that experience prolonged bed rest during hospitalization or institutionalization. Prophylactic measures to prevent loss of skeletal muscle in elderly people during prolonged periods of inactivity should be given a high priority. NIH PO1 AG023591, M01 RR14288

Developmental regulation of the activation of signaling components leading to translation initiation in skeletal muscle of neonatal pigs

The neonatal period is characterized by rapid growth driven by high rates of skeletal muscle protein synthesis. This high rate of protein synthesis declines with development. In this study, overnight fasted, 7 and 26 d. old pigs either remained fasting or were refed and the activation of growth factor- and nutrient-induced signaling components that regulate translation initiation were measured in skeletal muscle. Activation of the inhibitors of protein synthesis (PTEN, PP2A, and TSC2) increased with age (P<0.05). Neither the abundance nor the activation of AMPK, a potent inhibitor of protein synthesis, changed with age. Activation of positive regulators of protein synthesis (mTOR, S6K1 and 4EBP-1) decreased with age (P<0.05). Furthermore, raptor abundance and raptor-mTOR complex abundance were higher in 7- than in 26 d. old pigs (P<0.05), consistent with higher mTOR activation in younger pigs. The results suggest that the feeding-induced activation of growth factor and nutrient signaling components leading to mRNA translation initiation change with age and this likely contributes to the developmental decline in muscle protein synthesis. (NIH AR44474 and USDA 58-6250-001).

Developmental Regulation of Protein Kinase B Activation Is Isoform Specific in Skeletal Muscle of Neonatal Pigs

The postprandial activation of the insulin signaling pathway that leads to translation initiation is enhanced in skeletal muscle of the neonate and decreases with development in parallel with the developmental decline in muscle protein synthesis. Our previous study showed that the activity of protein kinase B (PKB), a major insulin signaling component, was higher in 7- than in 26-d-old pigs. To examine the molecular mechanisms involved, we determined PKB isoform abundance and phosphorylation state, the abundance of its kinases, and PKB's association with its kinases. The abundances of total PKB, PKBalpha, and PKBgamma were higher in muscle of 7- than in 26-d-old pigs whereas PKBbeta abundance was similar in the two age groups. PKB phosphorylation at Thr308 was higher in 7- than in 26-d-old pigs but PKB phosphorylation at Ser473 was similar in both age groups. The association of PKB with 3'-phosphoinositide-dependent kinase-1 (PDK-1), a kinase that phosphorylates PKB at Thr308, and PDK-1 abundance were higher in 7- than in 26-d-old pigs. Moreover, PDK-1 phosphorylation at Ser-241, a site that is crucial for PDK-1 activation, was higher in 7- than in 26-d-old pigs. However, the association of PKB with integrin-linked kinase (ILK), a kinase that potentially phosphorylates PKB at Ser473, and ILK abundance were similar in both age groups. The result suggests that the developmental change in PKB activation is isoform specific and involves regulation by PDK-1.

Insulin/Insulin-Like Growth Factor-I Hybrid Receptor Abundance Decreases with Development in Suckling Pigs

The activation of the insulin signaling pathway that leads to translation initiation is enhanced in skeletal muscle of neonates, and decreases with development in parallel with the developmental decline in muscle protein synthesis. Because the elevated expression of insulin receptor (IR)/insulin-like growth factor-I receptor (IGF-IR) hybrids has been associated with insulin resistance in some studies, we hypothesized that IR/IGF-IR hybrid abundance and binding affinity increase with development. To test this hypothesis, we determined the abundances and binding affinities of the IR, IGF-IR and hybrid receptor in skeletal muscle of 7- and 26-d-old pigs. We found that the abundances of IR, IGF-IR and hybrid receptor were higher in muscle of 7- than 26-d-old pigs. However, the relative proportions of hybrid receptor abundance compared with IR abundance and IGF-IR abundance were similar at both ages. The binding affinities of the IR, IGF-IR and hybrid receptor also were similar at both ages. Overall, the results suggest that insulin/IGF-I hybrid receptor abundance and binding affinity do not contribute to the developmental decline in the activation of the insulin signaling pathway.

Muscle protein turnover: methodological issues and the effect of aging.

Investigation of sarcopenia should include the measurement of muscle protein synthesis and breakdown because reduced muscle mass occurs only when muscle protein content is reduced. Protein content of a tissue is determined by the balance between synthesis and breakdown. Whole body measurements are inappropriate for determining the small changes in muscle protein synthesis and breakdown, since muscle contributes less than 30 percent to the whole body protein turnover. The measurement of mixed muscle protein synthesis in humans supports the animal data, which demonstrates that there is a decline in muscle protein synthesis with age. Resistance exercise stimulates mixed muscle protein synthesis rate in both the young and the old, although this is not demonstrated when myofibrillar protein synthesis is measured. Muscle is composed of several types of proteins, and their turnover may be differentially regulated. It is important, therefore, to measure the turnover of specific proteins such as myosin and actin, which are important contractile proteins. Recently, techniques have been developed to measure the synthesis rate of myosin heavy chain (MHC) in humans. In addition, the application of quantitative polymerase chain reaction (PCR) allows measurement of the steady state mRNA levels of various isoforms of MHC. These measurements, in combination with measurement of the synthesis rate of MHC, will allow us to understand the molecular regulation of specific proteins such as myosin. The important question is to determine whether the decline in muscle protein synthesis is genetically determined or secondary to inactivity, nutritional, hormonal, or other age-related alterations in body functions, and whether muscle wasting is reversible.(ABSTRACT TRUNCATED AT 250 WORDS)

Adaptation to prolonged starvation in the rat: curtailment of skeletal muscle proteolysis.

Previous studies have established that 16-wk-old nonobese and obese rats conserve body protein during prolonged starvation. To determine the basis for this, protein synthesis and degradation in skeletal muscle were evaluated in the isolated perfused hindquarters of these rats, in the fed state and when starved for 2, 5, 10, and 11 days. Rats aged 4 and 8 wk were used as a comparison. The results indicate that the response to starvation depends on several factors: the age of the rat, its degree of adiposity, and the duration of the fast. An early event in starvation was a decline in muscle protein synthesis. This occurred in all groups, albeit this reduction occurred more slowly in the older rats. A later response to starvation was an increase in muscle proteolysis. This occurred between 2 and 5 days in the 8-wk-old rats. In 16-wk-old rats it did not occur until between 5 and 10 days, and it was preceded by a period of decreased proteolysis. In 16-wk-old obese rats, a decrease in proteolysis persisted for upwards of 10 days and the secondary increase was not noted during the period of study. The data suggest that the ability of older and more obese rats to conserve body protein during starvation is due, in part, to a curtailment of muscle proteolysis. This adaptation seems to correlate with the availability of lipid fuels.