scholarly journals A model of muscle atrophy based on live microscopy of muscle remodelling in Drosophila metamorphosis

2016 ◽  
Vol 3 (2) ◽  
pp. 150517 ◽  
Author(s):  
Yadav Kuleesha ◽  
Wee Choo Puah ◽  
Martin Wasser
Keyword(s):  
Muscle Atrophy ◽  
Cell Biology ◽  
Muscle Wasting ◽  
Cathepsin L ◽  
Muscle Growth ◽  
Muscle Size ◽  
Abdominal Muscles ◽  
Quantitative Image ◽  
Muscle Remodelling

Genes controlling muscle size and survival play important roles in muscle wasting diseases. In Drosophila melanogaster metamorphosis, larval abdominal muscles undergo two developmental fates. While a doomed population is eliminated by cell death, another persistent group is remodelled and survives into adulthood. To identify and characterize genes involved in the development of remodelled muscles, we devised a workflow consisting of in vivo imaging, targeted gene perturbation and quantitative image analysis. We show that inhibition of TOR signalling and activation of autophagy promote developmental muscle atrophy in early, while TOR and yorkie activation are required for muscle growth in late pupation. We discovered changes in the localization of myonuclei during remodelling that involve anti-polar migration leading to central clustering followed by polar migration resulting in localization along the midline. We demonstrate that the Cathepsin L orthologue Cp1 is required for myonuclear clustering in mid, while autophagy contributes to central positioning of nuclei in late metamorphosis. In conclusion, studying muscle remodelling in metamorphosis can provide new insights into the cell biology of muscle wasting.

scholarly journals In Vitro, In Vivo, and In Silico Methods for Assessment of Muscle Size and Muscle Growth Regulation

Shock ◽  
2020 ◽  
Vol 53 (5) ◽  
pp. 605-615
Author(s):  
Joseph E. Rupert ◽  
Daenique H. A. Jengelley ◽  
Teresa A. Zimmers
Keyword(s):  
In Silico ◽  
Growth Regulation ◽  
Muscle Growth ◽  
Muscle Size ◽  
In Silico Methods

scholarly journals FOXO signaling is required for disuse muscle atrophy and is directly regulated by Hsp70

2010 ◽  
Vol 298 (1) ◽  
pp. C38-C45 ◽  
Author(s):  
Sarah M. Senf ◽  
Stephen L. Dodd ◽  
Andrew R. Judge
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Muscle Fiber ◽  
Muscle Wasting ◽  
Dominant Negative ◽  
Disuse Muscle Atrophy ◽  
Rat Soleus Muscle ◽  
Muscle Fiber Atrophy ◽  
Fiber Atrophy

The purpose of the current study was to determine whether heat shock protein 70 (Hsp70) directly regulates forkhead box O (FOXO) signaling in skeletal muscle. This aim stems from previous work demonstrating that Hsp70 overexpression inhibits disuse-induced FOXO transactivation and prevents muscle fiber atrophy. However, although FOXO is sufficient to cause muscle wasting, no data currently exist on the requirement of FOXO signaling in the progression of physiological muscle wasting, in vivo. In the current study we show that specific inhibition of FOXO, via expression of a dominant-negative FOXO3a, in rat soleus muscle during disuse prevented >40% of muscle fiber atrophy, demonstrating that FOXO signaling is required for disuse muscle atrophy. Subsequent experiments determined whether Hsp70 directly regulates FOXO3a signaling when independently activated in skeletal muscle, via transfection of FOXO3a. We show that Hsp70 inhibits FOXO3a-dependent transcription in a gene-specific manner. Specifically, Hsp70 inhibited FOXO3a-induced promoter activation of atrogin-1, but not MuRF1. Further studies showed that a FOXO3a DNA-binding mutant can activate MuRF1, but not atrogin-1, suggesting that FOXO3a activates these two genes through differential mechanisms. In summary, FOXO signaling is required for physiological muscle atrophy and is directly inhibited by Hsp70.

scholarly journals Differential regulation of actin and myosin isoenzyme synthesis in functionally overloaded skeletal muscle

1990 ◽  
Vol 265 (2) ◽  
pp. 525-532 ◽  
Author(s):  
P Gregory ◽  
J Gagnon ◽  
D A Essig ◽  
S K Reid ◽  
G Prior ◽  
...  
Keyword(s):  
Total Protein ◽  
Molecular Mechanisms ◽  
Muscle Growth ◽  
Muscle Size ◽  
Slow Myosin ◽  
Myosin Isoenzyme ◽  
Anterior Latissimus Dorsi ◽  
Fractional Synthesis

Overload hypertrophy of the chicken anterior latissimus dorsi muscle is accompanied by a replacement of one myosin isoenzyme (slow myosin-1, SM1) by another (slow myosin-2, SM2). To investigate the molecular mechanisms by which these changes occur, we measured the fractional synthesis rates (ks) in vivo of individual myosin-heavy-chain isoenzymes, total actin and total protein during the first 72 h of muscle growth. Although the ks of total protein and actin were doubled at 24 h, the ks for SM1 and SM2 were depressed. However, the ks of both isomyosins were nearly tripled by 72 h. Despite the increase in muscle size observed at 72 h, the amount of SM1 was reduced by half, indicating increased degradation of SM1. Results of translation of polyribosomes in vitro paralleled the results obtained in vivo. The proportion of total polyadenylylated mRNA in total RNA was increased at 48 and 72 h, but unchanged at 24 h despite the increase in protein synthesis at 24 h. Nuclease-protection analyses indicate that the level of specific SM1 and SM2 mRNAs change in a reciprocal fashion during overload. We conclude that gene-specific and temporal differences exist in the regulatory mechanisms that control overload-induced muscle growth.

Myostatin reduces Akt/TORC1/p70S6K signaling, inhibiting myoblast differentiation and myotube size

2009 ◽  
Vol 296 (6) ◽  
pp. C1258-C1270 ◽  
Author(s):  
Anne Ulrike Trendelenburg ◽  
Angelika Meyer ◽  
Daisy Rohner ◽  
Joseph Boyle ◽  
Shinji Hatakeyama ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Transforming Growth Factor ◽  
Negative Regulator ◽  
Bone Morphogenetic Protein 2 ◽  
Muscle Size ◽  
Skeletal Muscle Atrophy ◽  
Myoblast Differentiation ◽  
Activin Receptor

Myostatin is a negative regulator of skeletal muscle size, previously shown to inhibit muscle cell differentiation. Myostatin requires both Smad2 and Smad3 downstream of the activin receptor II (ActRII)/activin receptor-like kinase (ALK) receptor complex. Other transforming growth factor-β (TGF-β)-like molecules can also block differentiation, including TGF-β1, growth differentiation factor 11 (GDF-11), activins, bone morphogenetic protein 2 (BMP-2) and BMP-7. Myostatin inhibits activation of the Akt/mammalian target of rapamycin (mTOR)/p70S6 protein synthesis pathway, which mediates both differentiation in myoblasts and hypertrophy in myotubes. Blockade of the Akt/mTOR pathway, using small interfering RNA to regulatory-associated protein of mTOR (RAPTOR), a component of TOR signaling complex 1 (TORC1), increases myostatin-induced phosphorylation of Smad2, establishing a myostatin signaling-amplification role for blockade of Akt. Blockade of RAPTOR also facilitates myostatin's inhibition of muscle differentiation. Inhibition of TORC2, via rapamycin-insensitive companion of mTOR (RICTOR), is sufficient to inhibit differentiation on its own. Furthermore, myostatin decreases the diameter of postdifferentiated myotubes. However, rather than causing upregulation of the E3 ubiquitin ligases muscle RING-finger 1 ( MuRF1) and muscle atrophy F-box ( MAFbx), previously shown to mediate skeletal muscle atrophy, myostatin decreases expression of these atrophy markers in differentiated myotubes, as well as other genes normally upregulated during differentiation. These findings demonstrate that myostatin signaling acts by blocking genes induced during differentiation, even in a myotube, as opposed to activating the distinct “atrophy program.” In vivo, inhibition of myostatin increases muscle creatine kinase activity, coincident with an increase in muscle size, demonstrating that this in vitro differentiation measure is also upregulated in vivo.

Signaling in Muscle Atrophy and Hypertrophy

Physiology ◽  
2008 ◽  
Vol 23 (3) ◽  
pp. 160-170 ◽  
Author(s):  
Marco Sandri
Keyword(s):  
Physical Activity ◽  
Protein Synthesis ◽  
Growth Factors ◽  
Muscle Atrophy ◽  
Muscle Wasting ◽  
Muscle Growth ◽  
Neuromuscular Diseases ◽  
Muscle Performance ◽  
Prevention And Treatment ◽  
Atrophy And Hypertrophy

Muscle performance is influenced by turnover of contractile proteins. Production of new myofibrils and degradation of existing proteins is a delicate balance, which, depending on the condition, can promote muscle growth or loss. Protein synthesis and protein degradation are coordinately regulated by pathways that are influenced by mechanical stress, physical activity, availability of nutrients, and growth factors. Understanding the signaling that regulates muscle mass may provide potential therapeutic targets for the prevention and treatment of muscle wasting in metabolic and neuromuscular diseases.

scholarly journals Pharmacological Inhibition of HMGB1 Prevents Muscle Wasting

2021 ◽  
Vol 12 ◽  
Author(s):  
Lu Li ◽  
Huiquan Liu ◽  
Weili Tao ◽  
Su Wen ◽  
Xiaofen Fu ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Muscle Atrophy ◽  
Muscle Wasting ◽  
Expression Level ◽  
Soluble Form ◽  
C2c12 Myotubes ◽  
Hmgb1 Level ◽  
Related Proteins

Background: Cachexia is a multifactorial disorder characterized by weight loss and muscle wasting, making up for about 20% of cancer-related death. However, there are no effective drugs to combat cachexia at present.Methods: In this study, the effect of CT26 exosomes on C2C12 myotubes was observed. We compared serum HMGB1 level in cachexia and non-cachexia colon cancer patients. We further explored HMGB1 expression level in CT26 exosome. We added recombinant HMGB1 to C2C12 myotubes to observe the effects of HMGB1 on C2C12 myotubes and detected the expression level of the muscle atrophy-related proteins. Then, we used the HMGB1 inhibitor glycyrrhizin to reverse the effects of HMGB1 on C2C12 myotubes. Finally, HMGB1 inhibitor glycyrrhizin was utilized to relieve cachexia in CT26 cachexia mouse model.Results: Exosomes containing HMGB1 led to muscle atrophy with significantly decreased myotube diameter and increased expression of muscle atrophy-related proteins Atrogin1 and MuRF1. Further, we detected that HMGB1 induced the muscle atrophy mainly via TLR4/NF-κB pathway. Administration of the HMGB1 inhibitor glycyrrhizin could relieve muscle wasting in vitro and attenuate the progression of cachexia in vivo.Conclusion: These findings demonstrate the cachectic role of HMGB1, whether it is soluble form of HMGB1 or secreted from tumor cells as part of exosomes. HMGB1 inhibitor glycyrrhizin might be a promising drug in colon cancer cachexia.

scholarly journals Myostatin from the heart: local and systemic actions in cardiac failure and muscle wasting

2011 ◽  
Vol 300 (6) ◽  
pp. H1973-H1982 ◽  
Author(s):  
Astrid Breitbart ◽  
Mannix Auger-Messier ◽  
Jeffery D. Molkentin ◽  
Joerg Heineke
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Muscle Wasting ◽  
Muscle Growth ◽  
Skeletal Muscle Atrophy ◽  
Cardiac Cachexia ◽  
Heart Failure Patients ◽  
Skeletal Muscle Growth ◽  
Skeletal Muscle Wasting

A significant proportion of heart failure patients develop skeletal muscle wasting and cardiac cachexia, which is associated with a very poor prognosis. Recently, myostatin, a cytokine from the transforming growth factor-β (TGF-β) family and a known strong inhibitor of skeletal muscle growth, has been identified as a direct mediator of skeletal muscle atrophy in mice with heart failure. Myostatin is mainly expressed in skeletal muscle, although basal expression is also detectable in heart and adipose tissue. During pathological loading of the heart, the myocardium produces and secretes myostatin into the circulation where it inhibits skeletal muscle growth. Thus, genetic elimination of myostatin from the heart reduces skeletal muscle atrophy in mice with heart failure, whereas transgenic overexpression of myostatin in the heart is capable of inducing muscle wasting. In addition to its endocrine action on skeletal muscle, cardiac myostatin production also modestly inhibits cardiomyocyte growth under certain circumstances, as well as induces cardiac fibrosis and alterations in ventricular function. Interestingly, heart failure patients show elevated myostatin levels in their serum. To therapeutically influence skeletal muscle wasting, direct inhibition of myostatin was shown to positively impact skeletal muscle mass in heart failure, suggesting a promising strategy for the treatment of cardiac cachexia in the future.

scholarly journals Skeletal muscle wasting in chronic kidney disease: the emerging role of microRNAs

2019 ◽  
Vol 35 (9) ◽  
pp. 1469-1478 ◽  
Author(s):  
Kate A Robinson ◽  
Luke A Baker ◽  
Matthew P M Graham-Brown ◽  
Emma L Watson
Keyword(s):  
Skeletal Muscle ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Muscle Mass ◽  
Muscle Atrophy ◽  
Muscle Wasting ◽  
Muscle Growth ◽  
Exciting Field ◽  
Skeletal Muscle Wasting ◽  
And Function

Abstract Skeletal muscle wasting is a common complication of chronic kidney disease (CKD), characterized by the loss of muscle mass, strength and function, which significantly increases the risk of morbidity and mortality in this population. Numerous complications associated with declining renal function and lifestyle activate catabolic pathways and impair muscle regeneration, resulting in substantial protein wasting. Evidence suggests that increasing skeletal muscle mass improves outcomes in CKD, making this a clinically important research focus. Despite extensive research, the pathogenesis of skeletal muscle wasting is not completely understood. It is widely recognized that microRNAs (miRNAs), a family of short non-coding RNAs, are pivotal in the regulation of skeletal muscle homoeostasis, with significant roles in regulating muscle growth, regeneration and metabolism. The abnormal expression of miRNAs in skeletal muscle during disease has been well described in cellular and animal models of muscle atrophy, and in recent years, the involvement of miRNAs in the regulation of muscle atrophy in CKD has been demonstrated. As this exciting field evolves, there is emerging evidence for the involvement of miRNAs in a beneficial crosstalk system between skeletal muscle and other organs that may potentially limit the progression of CKD. In this article, we describe the pathophysiological mechanisms of muscle wasting and explore the contribution of miRNAs to the development of muscle wasting in CKD. We also discuss advances in our understanding of miRNAs in muscle–organ crosstalk and summarize miRNA-based therapeutics currently in clinical trials.

scholarly journals Live Imaging of muscle histolysis inDrosophilametamorphosis

2016 ◽  
Author(s):  
Yadav Kuleesha ◽  
Wee Choo Puah ◽  
Martin Wasser
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Cysteine Proteinase ◽  
Cathepsin L ◽  
Time Lapse ◽  
Live Imaging ◽  
Dominant Negative ◽  
Muscle Size ◽  
Genes Encoding

Background:The contribution of programmed cell death (PCD) to muscle wasting disorders remains a matter of debate.Drosophila melanogastermetamorphosis offers the opportunity to study muscle cell death in the context of development. Using live cell imaging of the abdomen, two groups of larval muscles can be observed, doomed muscles that undergo histolysis and persistent muscles that are remodelled and survive into adulthood.Method:To identify and characterize genes that control the decision between survival and cell death of muscles, we developed a method comprisingin vivoimaging, targeted gene perturbation and time-lapse image analysis. Our approach enabled us to study the cytological and temporal aspects of abnormal cell death phenotypes.Results:In a previous genetic screen for genes controlling muscle size and cell death in metamorphosis, we identified gene perturbations that induced cell death of persistent or inhibit histolysis of doomed larval muscles. RNA interference (RNAi) of the genes encoding the helicase Rm62 and the lysosomal Cathepsin-L homolog Cysteine proteinase 1 (Cp1) caused premature cell death of persistent muscle in early and mid-pupation, respectively. Silencing of the transcriptional co-repressorAtrophininhibited histolysis of doomed muscles. Overexpression of dominant-negative Target of Rapamycin (TOR) delayed the histolysis of a subset of doomed and induced ablation of all persistent muscles. RNAi ofAMPKα,which encodes a subunit of the AMPK protein complex that senses AMP and promotes ATP formation, led to loss of attachment and a spherical morphology. None of the perturbations affected the survival of newly formed adult muscles, suggesting that the method is useful to find genes that are crucial for the survival of metabolically challenged muscles, like those undergoing atrophy. The ablation of persistent muscles did not affect eclosion of adult flies.Conclusions:Live imaging is a versatile approach to uncover gene functions that are required for the survival of muscle undergoing remodelling, yet are dispensable for other adult muscles. Our approach promises to identify molecular mechanisms that can explain the resilience of muscles to PCD.

scholarly journals IGF-1 prevents ANG II-induced skeletal muscle atrophy via Akt- and Foxo-dependent inhibition of the ubiquitin ligase atrogin-1 expression

2010 ◽  
Vol 298 (5) ◽  
pp. H1565-H1570 ◽  
Author(s):  
Tadashi Yoshida ◽  
Laura Semprun-Prieto ◽  
Sergiy Sukhanov ◽  
Patrice Delafontaine
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Muscle Wasting ◽  
Critical Role ◽  
Ring Finger ◽  
Dominant Negative ◽  
Skeletal Muscle Atrophy ◽  
Ang Ii ◽  
Skeletal Muscle Wasting

Congestive heart failure is associated with activation of the renin-angiotensin system and skeletal muscle wasting. Angiotensin II (ANG II) has been shown to increase muscle proteolysis and decrease circulating and skeletal muscle IGF-1. We have shown previously that skeletal muscle-specific overexpression of IGF-1 prevents proteolysis and apoptosis induced by ANG II. These findings indicated that downregulation of IGF-1 signaling in skeletal muscle played an important role in the wasting effect of ANG II. However, the signaling pathways and mechanisms whereby IGF-1 prevents ANG II-induced skeletal muscle atrophy are unknown. Here we show ANG II-induced transcriptional regulation of two ubiquitin ligases atrogin-1 and muscle ring finger-1 (MuRF-1) that precedes the reduction of skeletal muscle IGF-1 expression, suggesting that activation of atrogin-1 and MuRF-1 is an initial mechanism leading to skeletal muscle atrophy in response to ANG II. IGF-1 overexpression in skeletal muscle prevented ANG II-induced skeletal muscle wasting and the expression of atrogin-1, but not MuRF-1. Dominant-negative Akt and constitutively active Foxo-1 blocked the ability of IGF-1 to prevent ANG II-mediated upregulation of atrogin-1 and skeletal muscle wasting. Our findings demonstrate that the ability of IGF-1 to prevent ANG II-induced skeletal muscle wasting is mediated via an Akt- and Foxo-1-dependent signaling pathway that results in inhibition of atrogin-1 but not MuRF-1 expression. These data suggest strongly that atrogin-1 plays a critical role in mechanisms of ANG II-induced wasting in vivo.

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