scholarly journals Muscle-specific and age-related changes in protein synthesis and protein degradation in response to hindlimb unloading in rats

2017 ◽  
Vol 122 (5) ◽  
pp. 1336-1350 ◽  
Author(s):  
Leslie M. Baehr ◽  
Daniel W. D. West ◽  
Andrea G. Marshall ◽  
George R. Marcotte ◽  
Keith Baar ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Protein Degradation ◽  
Muscle Mass ◽  
Muscle Atrophy ◽  
Molecular Mechanisms ◽  
Fiber Type ◽  
Hindlimb Unloading ◽  
Medial Gastrocnemius ◽  
Old Rats ◽  
The Impact

Disuse is a potent inducer of muscle atrophy, but the molecular mechanisms driving this loss of muscle mass are highly debated. In particular, the extent to which disuse triggers decreases in protein synthesis or increases in protein degradation, and whether these changes are uniform across muscles or influenced by age, is unclear. We aimed to determine the impact of disuse on protein synthesis and protein degradation in lower limb muscles of varied function and fiber type in adult and old rats. Alterations in protein synthesis and degradation were measured in the soleus, medial gastrocnemius, and tibialis anterior (TA) muscles of adult and old rats subjected to hindlimb unloading (HU) for 3, 7, or 14 days. Loss of muscle mass was progressive during the unloading period, but highly variable (−9 to −38%) across muscle types and between ages. Protein synthesis decreased significantly in all muscles, except for the old TA. Atrophy-associated gene expression was only loosely associated with protein degradation as muscle RING finger-1, muscle atrophy F-box (MAFbx), and Forkhead box O1 expression significantly increased in all muscles, but an increase in proteasome activity was only observed in the adult soleus. MAFbx protein levels were significantly higher in the old muscles compared with adult muscles, despite the old having higher expression of microRNA-23a. These results indicate that adult and old muscles respond similarly to HU, and the greatest loss in muscle mass occurs in predominantly slow-twitch extensor muscles due to a concomitant decrease in protein synthesis and increase in protein degradation. NEW & NOTEWORTHY In this study, we showed that age did not intensify the atrophy response to unloading in rats, but rather that the degree of atrophy was highly variable across muscles, indicating that changes in protein synthesis and protein degradation occur in a muscle-specific manner. Our data emphasize the importance of studying muscles of varying fiber-type and physiological function at multiple time points to fully understand the molecular mechanisms responsible for disuse atrophy.

scholarly journals Involvement of AMPK in regulating slow-twitch muscle atrophy during hindlimb unloading in mice

2015 ◽  
Vol 309 (7) ◽  
pp. E651-E662 ◽  
Author(s):  
Tatsuro Egawa ◽  
Ayumi Goto ◽  
Yoshitaka Ohno ◽  
Shingo Yokoyama ◽  
Akihiro Ikuta ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Degradation ◽  
Muscle Mass ◽  
Muscle Atrophy ◽  
Skeletal Muscle Mass ◽  
Ubiquitin Proteasome System ◽  
Hindlimb Unloading ◽  
Slow Twitch Muscle ◽  
Ubiquitin Proteasome ◽  
Slow Twitch

AMPK is considered to have a role in regulating skeletal muscle mass. However, there are no studies investigating the function of AMPK in modulating skeletal muscle mass during atrophic conditions. In the present study, we investigated the difference in unloading-associated muscle atrophy and molecular functions in response to 2-wk hindlimb suspension between transgenic mice overexpressing the dominant-negative mutant of AMPK (AMPK-DN) and their wild-type (WT) littermates. Male WT ( n = 24) and AMPK-DN ( n = 24) mice were randomly divided into two groups: an untreated preexperimental control group ( n = 12 in each group) and an unloading ( n = 12 in each group) group. The relative soleus muscle weight and fiber cross-sectional area to body weight were decreased by ∼30% in WT mice by hindlimb unloading and by ∼20% in AMPK-DN mice. There were no changes in puromycin-labeled protein or Akt/70-kDa ribosomal S6 kinase signaling, the indicators of protein synthesis. The expressions of ubiquitinated proteins and muscle RING finger 1 mRNA and protein, markers of the ubiquitin-proteasome system, were increased by hindlimb unloading in WT mice but not in AMPK-DN mice. The expressions of molecules related to the protein degradation system, phosphorylated forkhead box class O3a, inhibitor of κBα, microRNA (miR)-1, and miR-23a, were decreased only in WT mice in response to hindlimb unloading, and 72-kDa heat shock protein expression was higher in AMPK-DN mice than in WT mice. These results imply that AMPK partially regulates unloading-induced atrophy of slow-twitch muscle possibly through modulation of the protein degradation system, especially the ubiquitin-proteasome system.

scholarly journals Transcriptome analysis of gravitational effects on mouse skeletal muscles under microgravity and artificial 1 g onboard environment

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Risa Okada ◽  
Shin-ichiro Fujita ◽  
Riku Suzuki ◽  
Takuto Hayashi ◽  
Hirona Tsubouchi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Muscle Mass ◽  
Muscle Atrophy ◽  
Transcriptome Analysis ◽  
Fiber Type ◽  
Expression Profiles ◽  
Space Station ◽  
Gene Expression Profiles

AbstractSpaceflight causes a decrease in skeletal muscle mass and strength. We set two murine experimental groups in orbit for 35 days aboard the International Space Station, under artificial earth-gravity (artificial 1 g; AG) and microgravity (μg; MG), to investigate whether artificial 1 g exposure prevents muscle atrophy at the molecular level. Our main findings indicated that AG onboard environment prevented changes under microgravity in soleus muscle not only in muscle mass and fiber type composition but also in the alteration of gene expression profiles. In particular, transcriptome analysis suggested that AG condition could prevent the alterations of some atrophy-related genes. We further screened novel candidate genes to reveal the muscle atrophy mechanism from these gene expression profiles. We suggest the potential role of Cacng1 in the atrophy of myotubes using in vitro and in vivo gene transductions. This critical project may accelerate the elucidation of muscle atrophy mechanisms.

scholarly journals Differential protein metabolism and regeneration in hypertrophic diaphragm and atrophic gastrocnemius muscles in hibernating Daurian ground squirrels

2019 ◽  
Author(s):  
Xia Yan ◽  
Xuli Gao ◽  
Xin Peng ◽  
Jie Zhang ◽  
Xiufeng Ma ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Protein Degradation ◽  
Muscle Regeneration ◽  
Protein Metabolism ◽  
Muscle Hypertrophy ◽  
Gastrocnemius Muscle ◽  
Fiber Type ◽  
Ground Squirrels ◽  
Diaphragm Muscle ◽  
Gastrocnemius Muscles

AbstractWhether differences in regulation of protein metabolism and regeneration are involved in the different phenotypic adaptation mechanisms of muscle hypertrophy and atrophy in hibernators? Two fast-type muscles (diaphragm and gastrocnemius) in summer active and hibernating Daurian ground squirrels were selected to detect changes in cross-sectional area (CSA), fiber type distribution, and protein expression indicative of protein synthesis metabolism (protein expression of P-Akt, P-mTORC1, P-S6K1, and P-4E-BP1), protein degradation metabolism (MuRF1, atrogin-1, calpain-1, calpain-2, calpastatin, desmin, troponin T, Beclin1, and LC3-II), and muscle regeneration (MyoD, myogenin, and myostatin). Results showed the CSA of the diaphragm muscle increased significantly by 26.1%, whereas the CSA of the gastrocnemius muscle decreased significantly by 20.4% in the hibernation group compared with the summer active group. Both muscles displayed a significant fast-to-slow fiber-type transition in hibernation. Our study further indicated that increased protein synthesis, decreased protein degradation, and increased muscle regeneration potential contributed to diaphragm muscle hypertrophy, whereas decreased protein synthesis, increased protein degradation, and decreased muscle regeneration potential contributed to gastrocnemius muscle atrophy. In conclusion, the differences in muscle regeneration and regulatory pattern of protein metabolism may contribute to the different adaptive changes observed in the diaphragm and gastrocnemius muscles of ground squirrels.

Glutamine prevents downregulation of myosin heavy chain synthesis and muscle atrophy from glucocorticoids

1995 ◽  
Vol 268 (4) ◽  
pp. E730-E734 ◽  
Author(s):  
R. C. Hickson ◽  
S. M. Czerwinski ◽  
L. E. Wegrzyn
Keyword(s):  
Protein Synthesis ◽  
Myosin Heavy Chain ◽  
Muscle Mass ◽  
Muscle Atrophy ◽  
Heavy Chain ◽  
Total Protein ◽  
Female Rats ◽  
Glucocorticoid Treatment ◽  
Precursor Pool ◽  
Chain Synthesis

The aims of this study were to determine whether glutamine infusion prevents the decline in protein synthesis and muscle wasting associated with repeated glucocorticoid treatment. Hormone (cortisol acetate, 100 mg.kg body wt-1.day-1) and vehicle (carboxymethyl cellulose)-treated female rats were infused with either saline or glutamine (240 mM, 0.75 ml/h) for a 7-day period. Glutamine infusion attenuated the decline of plantaris muscle glutamine concentration (3.0 +/- 0.2 vs. 2.3 +/- 0.2 mumol/g) and prevented > 70% of the total muscle mass losses due to the glucocorticoid injections. Fractional synthesis rates of myosin heavy chain (MHC) and total protein were determined after constant [3H]leucine infusion from the leucyl-tRNA precursor pool, which was similar in all groups (range 4.8 +/- 0.5 to 6.3 +/- 0.4 disintegrations.min-1.pmol-1). MHC synthesis rates (%/day) in plantaris muscles were reduced to approximately 40% of controls (4.2/9.4). Although glutamine had no effect on MHC synthesis in vehicle-treated animals (10.1/9.4), it prevented 50% (7.6/4.2) of the hormone-induced decline in MHC synthesis rates. The same results were obtained with total protein synthesis measurements. Changes in muscle mass did not appear related to estimates of protein breakdown. In conclusion, these data show that glutamine infusion is effective therapy in counteracting glucocorticoid-induced muscle atrophy. Atrophy attenuation appears related to maintaining muscle glutamine levels, which in turn may limit the glucocorticoid-mediated downregulation of MHC synthesis.

Mechanical stimulation of the plantar foot surface attenuates soleus muscle atrophy induced by hindlimb unloading in rats

2005 ◽  
Vol 99 (2) ◽  
pp. 739-746 ◽  
Author(s):  
Antonios Kyparos ◽  
Daniel L. Feeback ◽  
Charles S. Layne ◽  
Daniel A. Martinez ◽  
Mark S. F. Clarke
Keyword(s):  
Muscle Atrophy ◽  
Soleus Muscle ◽  
Gastrocnemius Muscle ◽  
Hindlimb Unloading ◽  
Medial Gastrocnemius ◽  
Type I ◽  
Cross Sectional ◽  
Plantar Surface ◽  
Male Wistar Rats ◽  
Medial Gastrocnemius Muscle

Unloading-induced muscle atrophy occurs in the aging population, bed-ridden patients, and astronauts. This study was designed to determine whether dynamic foot stimulation (DFS) applied to the plantar surface of the rat foot can serve as a countermeasure to soleus muscle atrophy normally observed in hindlimb unloaded (HU) rats. Forty-four mature (6 mo old), male Wistar rats were randomly assigned to ambulatory control, HU alone, HU with active DFS (i.e., plantar contact with active inflation), HU with passive DFS (i.e., plantar contact without active inflation), and HU while wearing a DFS boot with no plantar contact groups. Application of active DFS during HU significantly counteracted the atrophic response by preventing ∼85% of the reduction in type I myofiber cross-sectional area (CSA) in the soleus while preventing ∼57% of the reduction in type I myofiber CSA and 43% of the reduction in type IIA myofiber CSA of the medial gastrocnemius muscle. Wearing of a DFS boot without active inflation prevented myofiber atrophy in the soleus of HU animals in a fashion similar to that observed in HU animals that wore an actively inflated DFS boot. However, when a DFS boot without plantar surface contact was worn during HU, no significant protection from HU-induced myofiber atrophy was observed. These results illustrate that the application of mechanical foot stimulation to the plantar surface of the rat foot is an effective countermeasure to muscle atrophy induced by HU.

scholarly journals Amyotrophy Induced by a High-Fat Diet Is Closely Related to Inflammation and Protein Degradation Determined by Quantitative Phosphoproteomic Analysis in Skeletal Muscle of C57BL/6 J Mice

2019 ◽  
Vol 150 (2) ◽  
pp. 294-302
Author(s):  
Ya-nan Sun ◽  
Jia-qiang Huang ◽  
Zhong-zhou Chen ◽  
Min Du ◽  
Fa-zheng Ren ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Body Weight ◽  
Protein Kinase ◽  
Glucose Metabolism ◽  
Protein Degradation ◽  
Muscle Atrophy ◽  
High Fat Diet ◽  
Molecular Mechanisms ◽  
Serum Glucose ◽  
High Fat

ABSTRACT Background Ectopic fat accumulation in skeletal muscle results in dysfunction and atrophy, but the underlying molecular mechanisms remain unclear. Objective The aim of this study was to investigate the effects of a high-fat diet (HFD) in modulating the structure and energy metabolism of skeletal muscle and the underlying mechanisms in mice. Methods Four-week-old male C57BL/6 J mice (n = 30) were allowed 1 wk for acclimatization. After 6 mice with low body weight were removed from the study, the remaining 24 mice were fed with a normal-fat diet (NFD; 10% energy from fat, n = 12) or an HFD (60% energy from fat, n = 12) for 24 wk. At the end of the experiment, serum glucose and lipid concentrations were measured, and skeletal muscle was collected for atrophy analysis, inflammation measurements, and phosphoproteomic analysis. Results Compared with the NFD, the HFD increased (P < 0.05) body weight (35.8%), serum glucose (64.5%), and lipid (27.3%) concentrations, along with elevated (P < 0.05) expressions of the atrophy-related proteins muscle ring finger 1 (MURF1; 27.6%) and muscle atrophy F-box (MAFBX; 44.5%) in skeletal muscle. Phosphoproteomic analysis illustrated 64 proteins with differential degrees of phosphorylation between the HFD and NFD groups. These proteins were mainly involved in modulating cytoskeleton [adenylyl cyclase-associated protein 2 (CAP2) and actin-α skeletal muscle (ACTA1)], inflammation [NF-κB-activating protein (NKAP) and serine/threonine-protein kinase RIO3 (RIOK3)], glucose metabolism [Cdc42-interacting protein 4 (TRIP10); protein kinase C, and casein kinase II substrate protein 3 (PACSIN3)], and protein degradation [heat shock protein 90 kDa (HSP90AA1)]. The HFD-induced inhibitions of the insulin signaling pathway and activations of inflammation in skeletal muscle were verified by Western blot analysis. Conclusions Quantitative phosphoproteomic analysis in C57BL/6 J mice fed an NFD or HFD for 24 wk revealed that the phosphorylation of inflammatory proteins and proteins associated with glucose metabolism at specific serine residues may play critical roles in the regulation of skeletal muscle atrophy induced by an HFD. This work provides information regarding underlying molecular mechanisms for inflammation-induced dysfunction and atrophy in skeletal muscle.

Regulation of translation factors during hindlimb unloading and denervation of skeletal muscle in rats

2001 ◽  
Vol 281 (1) ◽  
pp. C179-C187 ◽  
Author(s):  
Troy A. Hornberger ◽  
R. Bridge Hunter ◽  
Susan C. Kandarian ◽  
Karyn A. Esser
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Muscle Atrophy ◽  
Protein Translation ◽  
Hindlimb Unloading ◽  
Initiation Factor ◽  
Skeletal Muscle Atrophy ◽  
Α Subunit ◽  
Translation Factors ◽  
Ribosomal S6 Kinase

In the rat, denervation and hindlimb unloading are two commonly employed models used to study skeletal muscle atrophy. In these models, muscle atrophy is generally produced by a decrease in protein synthesis and an increase in protein degradation. The decrease in protein synthesis has been suggested to occur by an inhibition at the level of protein translation. To better characterize the regulation of protein translation, we investigated the changes that occur in various translation initiation and elongation factors. We demonstrated that both hindlimb unloading and denervation produce alterations in the phosphorylation and/or total amount of the 70-kDa ribosomal S6 kinase, eukaryotic initiation factor 2 α-subunit, and eukaryotic elongation factor 2. Our findings indicate that the regulation of these protein translation factors differs between the models of atrophy studied and between the muscles evaluated (e.g., soleus vs. extensor digitorum longus).

scholarly journals Glucocorticoid effects on insulin- and IGF-I-regulated muscle protein metabolism during aging

1998 ◽  
Vol 156 (1) ◽  
pp. 83-89 ◽  
Author(s):  
D Dardevet ◽  
C Sornet ◽  
I Savary ◽  
E Debras ◽  
P Patureau-Mirand ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Muscle Atrophy ◽  
Protein Metabolism ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Recovery Period ◽  
Adult Rats ◽  
Igf I ◽  
Muscle Protein Metabolism ◽  
Old Rats

This study was performed to assess the effect of glucocorticoids (dexamethasone) on insulin- and IGF-I-regulated muscle protein metabolism in adult and old rats. Muscle atrophy occurred more rapidly in old rats, and recovery of muscle mass was impaired when compared with adults. Muscle wasting resulted mainly from increased protein breakdown in adult rat but from depressed protein synthesis in the aged animal. Glucocorticoid treatment significantly decreased the stimulatory effect of insulin and IGF-I on muscle protein synthesis in adult rats by 25.9 and 58.1% respectively. In old rats, this effect was even greater, being 49.3 and 100% respectively. With regard to muscle proteolysis, glucocorticoids blunted the anti-proteolytic action of insulin and IGF-I in both age groups. During the recovery period, adult rats reversed the glucocorticoid-induced resistance of muscle protein metabolism within 3 days, at which time old rats still exhibited the decrease in insulin-regulated proteolysis. In conclusion, the higher sensitivity of old rat muscle to glucocorticoids may in part result from the greater modification of the effects of insulin and IGF-I on muscle protein metabolism. These responses to glucocorticoids in old rats may be associated with the emergence of muscle atrophy with advancing age.

scholarly journals MuRF1/TRIM63, Master Regulator of Muscle Mass

2020 ◽  
Vol 21 (18) ◽  
pp. 6663 ◽  
Author(s):  
Dulce Peris-Moreno ◽  
Daniel Taillandier ◽  
Cécile Polge
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Muscle Atrophy ◽  
Molecular Mechanisms ◽  
Muscle Wasting ◽  
Skeletal Muscle Atrophy ◽  
Cardiac Functions ◽  
Important Player ◽  
Cardiac Muscles ◽  
Inhibitory Molecules

The E3 ubiquitin ligase MuRF1/TRIM63 was identified 20 years ago and suspected to play important roles during skeletal muscle atrophy. Since then, numerous studies have been conducted to decipher the roles, molecular mechanisms and regulation of this enzyme. This revealed that MuRF1 is an important player in the skeletal muscle atrophy process occurring during catabolic states, making MuRF1 a prime candidate for pharmacological treatments against muscle wasting. Indeed, muscle wasting is an associated event of several diseases (e.g., cancer, sepsis, diabetes, renal failure, etc.) and negatively impacts the prognosis of patients, which has stimulated the search for MuRF1 inhibitory molecules. However, studies on MuRF1 cardiac functions revealed that MuRF1 is also cardioprotective, revealing a yin and yang role of MuRF1, being detrimental in skeletal muscle and beneficial in the heart. This review discusses data obtained on MuRF1, both in skeletal and cardiac muscles, over the past 20 years, regarding the structure, the regulation, the location and the different functions identified, and the first inhibitors reported, and aim to draw the picture of what is known about MuRF1. The review also discusses important MuRF1 characteristics to consider for the design of future drugs to maintain skeletal muscle mass in patients with different pathologies.

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