Dataset Information

Muscle-specific changes in protein synthesis with aging and reloading after disuse atrophy.

ABSTRACT:

Background

Successful strategies to halt or reverse sarcopenia require a basic understanding of the factors that cause muscle loss with age. Acute periods of muscle loss in older individuals have an incomplete recovery of muscle mass and strength, thus accelerating sarcopenic progression. The purpose of the current study was to further understand the mechanisms underlying the failure of old animals to completely recover muscle mass and function after a period of hindlimb unloading.

Methods

Hindlimb unloading was used to induce muscle atrophy in Fischer 344-Brown Norway (F344BN F1) rats at 24, 28, and 30 months of age. Rats were hindlimb unloaded for 14 days and then reloaded at 24 months (Reloaded 24), 28 months (Reloaded 28), and 24 and 28 months (Reloaded 24/28) of age. Isometric torque was determined at 24 months of age (24 months), at 28 months of age (28 months), immediately after 14 days of reloading, and at 30 months of age (30 months). During control or reloaded conditions, rats were labelled with deuterium oxide (D₂ O) to determine rates of muscle protein synthesis and RNA synthesis.

Results

After 14 days of reloading, in vivo isometric torque returned to baseline in Reloaded 24, but not Reloaded 28 and Reloaded 24/28. Despite the failure of Reloaded 28 and Reloaded 24/28 to regain peak force, all groups were equally depressed in peak force generation at 30 months. Increased age did not decrease muscle protein synthesis rates, and in fact, increased resting rates of protein synthesis were measured in the myofibrillar fraction (Fractional synthesis rate (FSR): %/day) of the plantaris (24 months: 2.53 ± 0.17; 30 months: 3.29 ± 0.17), and in the myofibrillar (24 months: 2.29 ± 0.07; 30 months: 3.34 ± 0.11), collagen (24 months: 1.11 ± 0.07; 30 months: 1.55 ± 0.14), and mitochondrial (24 months: 2.38 ± 0.16; 30 months: 3.20 ± 0.10) fractions of the tibialis anterior (TA). All muscles increased myofibrillar protein synthesis (%/day) in Reloaded 24 (soleus: 3.36 ± 0.11, 5.23 ± 0.19; plantaris: 2.53 ± 0.17, 3.66 ± 0.07; TA: 2.29 ± 0.14, 3.15 ± 0.12); however, in Reloaded 28, only the soleus had myofibrillar protein synthesis rates (%/day) >28 months (28 months: 3.80 ± 0.10; Reloaded 28: 4.86 ± 0.19). Across the muscles, rates of protein synthesis were correlated with RNA synthesis (all muscles combined, R² = 0.807, P < 0.0001).

Conclusions

These data add to the growing body of literature that indicate that changes with age, including following disuse atrophy, differ by muscle. In addition, our findings lead to additional questions of the underlying mechanisms by which some muscles are maintained with age while others are not.

SUBMITTER: Miller BF

PROVIDER: S-EPMC6903438 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Muscle-specific changes in protein synthesis with aging and reloading after disuse atrophy.

Miller Benjamin F BF Baehr Leslie M LM Musci Robert V RV Reid Justin J JJ Peelor Frederick F FF Hamilton Karyn L KL Bodine Sue C SC

Journal of cachexia, sarcopenia and muscle 20190716 6

<h4>Background</h4>Successful strategies to halt or reverse sarcopenia require a basic understanding of the factors that cause muscle loss with age. Acute periods of muscle loss in older individuals have an incomplete recovery of muscle mass and strength, thus accelerating sarcopenic progression. The purpose of the current study was to further understand the mechanisms underlying the failure of old animals to completely recover muscle mass and function after a period of hindlimb unloading.<h4>Me ...[more]

PMID: 31313502

Similar Datasets

Project description:BackgroundSkeletal muscle mass and strength diminish during periods of disuse but recover upon return to weight bearing in healthy adults but are incomplete in old muscle. Efforts to improve muscle recovery in older individuals commonly aim at increasing myofibrillar protein synthesis via mammalian target of rapamycin (mTOR) stimulation despite evidence demonstrating that old muscle has chronically elevated levels of mammalian target of rapamycin complex 1 (mTORC1) activity. We hypothesized that protein synthesis is higher in old muscle than adult muscle, which contributes to a proteostatic stress that impairs recovery.MethodsWe unloaded hindlimbs of adult (10-month) and old (28-month) F344BN rats for 14 days to induce atrophy, followed by reloading up to 60 days with deuterium oxide (D2 O) labelling to study muscle regrowth and proteostasis.ResultsWe found that old muscle has limited recovery of muscle mass during reloading despite having higher translational capacity and myofibrillar protein synthesis (0.029 k/day ± 0.002 vs. 0.039 k/day ± 0.002, P < 0.0001) than adult muscle. We showed that collagen protein synthesis was not different (0.005 k (1/day) ± 0.0005 vs. 0.004 k (1/day) ± 0.0005, P = 0.15) in old compared to adult, but old muscle had higher collagen concentration (4.5 μg/mg ± 1.2 vs. 9.8 μg/mg ± 0.96, P < 0.01), implying that collagen breakdown was slower in old muscle than adult muscle. This finding was supported by old muscle having more insoluble collagen (4.0 ± 1.1 vs. 9.2 ± 0.9, P < 0.01) and an accumulation of advanced glycation end products (1.0 ± 0.06 vs. 1.5 ± 0.08, P < 0.001) than adult muscle during reloading. Limited recovery of muscle mass during reloading is in part due to higher protein degradation (0.017 1/t ± 0.002 vs. 0.028 1/t ± 0.004, P < 0.05) and/or compromised proteostasis as evidenced by accumulation of ubiquitinated insoluble proteins (1.02 ± 0.06 vs. 1.22 ± 0.06, P < 0.05). Last, we showed that synthesis of individual proteins related to protein folding/refolding, protein degradation and neural-related biological processes was higher in old muscle during reloading than adult muscle.ConclusionsOur data suggest that the failure of old muscle to recover after disuse is not due to limitations in the ability to synthesize myofibrillar proteins but because of other impaired proteostatic mechanisms (e.g., protein folding and degradation). These data provide novel information on individual proteins that accumulate in protein aggregates after disuse and certain biological processes such as protein folding and degradation that likely play a role in impaired recovery. Therefore, interventions to enhance regrowth of old muscle after disuse should be directed towards the identified impaired proteostatic mechanisms and not aimed at increasing protein synthesis.

Project description:Short-term disuse leads to muscle loss driven by lowered daily myofibrillar protein synthesis (MyoPS). However, disuse commonly results from muscle damage, and its influence on muscle deconditioning during disuse is unknown. Twenty-one males [20 ± 1 yr, BMI = 24 ± 1 kg·m-2 (± SE)] underwent 7 days of unilateral leg immobilization immediately preceded by 300 bilateral, maximal, muscle-damaging eccentric quadriceps contractions (DAM; subjects n = 10) or no exercise (CON; subjects n = 11). Participants ingested deuterated water and underwent temporal bilateral thigh MRI scans and vastus lateralis muscle biopsies of immobilized (IMM) and nonimmobilized (N-IMM) legs. N-IMM quadriceps muscle volume remained unchanged throughout both groups. IMM quadriceps muscle volume declined after 2 days by 1.7 ± 0.5% in CON (P = 0.031; and by 1.3 ± 0.6% when corrected to N-IMM; P = 0.06) but did not change in DAM, and declined equivalently in CON [by 6.4 ± 1.1% (5.0 ± 1.6% when corrected to N-IMM)] and DAM [by 2.6 ± 1.8% (4.0 ± 1.9% when corrected to N-IMM)] after 7 days. Immobilization began to decrease MyoPS compared with N-IMM in both groups after 2 days (P = 0.109), albeit with higher MyoPS rates in DAM compared with CON (P = 0.035). Frank suppression of MyoPS was observed between days 2 and 7 in CON (IMM = 1.04 ± 0.12, N-IMM = 1.86 ± 0.10%·day-1; P = 0.002) but not DAM (IMM = 1.49 ± 0.29, N-IMM = 1.90 ± 0.30%·day-1; P > 0.05). Declines in MyoPS and quadriceps volume after 7 days correlated positively in CON (r2 = 0.403; P = 0.035) but negatively in DAM (r2 = 0.483; P = 0.037). Quadriceps strength declined following immobilization in both groups, but to a greater extent in DAM. Prior muscle-damaging eccentric exercise increases MyoPS and prevents loss of quadriceps muscle volume after 2 (but not 7) days of disuse.NEW & NOTEWORTHY We investigated the impact of prior muscle-damaging eccentric exercise on disuse-induced muscle deconditioning. Two and 7 days of muscle disuse per se lowered quadriceps muscle volume in association with lowered daily myofibrillar protein synthesis (MyoPS). Prior eccentric exercise prevented the decline in muscle volume after 2 days and attenuated the decline in MyoPS after 2 and 7 days. These data indicate eccentric exercise increases MyoPS and transiently prevents quadriceps muscle atrophy during muscle disuse.

Project description:Skeletal muscle atrophy is a consequence of many diseases, environmental insults, inactivity, age and injury. Atrophy is characterized by active degradation and removal of contractile proteins and a reduction in fiber size. Animal models have been extensively used to identify pathways leading to atrophic conditions. Here we have used genome-wide expression profiling analysis and quantitative PCR to identify the molecular changes that occur in two clinically relevant animal mouse models of muscle atrophy, hindlimb casting and Achilles tendon laceration (tenotomy). Gastrocnemius muscle samples were collected 2, 7 and 14 days after insult. The total amount of muscle loss as measured by wet weight and muscle fiber size was equivalent between models, although tenotomy resulted in a more rapid induction of muscle atrophy. Furthermore, tentomy resulted in the regulation of significantly more mRNA transcripts then casting. Analysis of the regulated genes and pathways suggest that the mechanism of atrophy is distinct between these models. The degradation following casting appears ubiquitin-proteasome-mediated while degradation following tenotomy appears lysosomal and matrix-metalloproteinase (MMP)-mediated. This data suggests that there are multiple mechanisms leading to muscle atrophy and that specific therapeutic agents may be necessary to combat the atrophy seen under different conditions. Muscle atrophy was induced through two methods; unloading induced by tendon laceration (Tenotomy) and immobilization induced by hindlimb casting (Casting). For the tenotomy, eight week old male C57/B6 mice were anesthetized by ether inhalation and subsequent intramuscular injection of ketamine-xylazine (0.1 ml/g). The right Achilles tendon just proximal to the calcaneus was severed with a sterile scalpel. The mice were allowed to recover and move freely about their cage. An additional cohort of animals was sham operated (Sham) which involved isolation and manipulation of the Achilles tendon without laceration. For the casting, the right hindlimbs of eight week old male C57Bl/6 mice were immobilized through casting. After 2, 7 or 14 days, animals were sacrificed and the left and right gastrocnemius muscles were carefully removed, flash frozen in liquid nitrogen, and stored at -80°C for further processing. The left untreated legs served as controls. A group of naïve animals that received no treatment or manipulation was included as an additional control. Each group consisted of between 5 and 10 samples for a total of 111 individual samples.

Dataset Information

Muscle-specific changes in protein synthesis with aging and reloading after disuse atrophy.

Background

Methods

Results

Conclusions

Publications

Muscle-specific changes in protein synthesis with aging and reloading after disuse atrophy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets