The ubiquitin–proteasome system and skeletal muscle wasting

2005 ◽  
Vol 41 (1) ◽  
pp. 173 ◽  
Author(s):  
Didier Attaix ◽  
Sophie Ventadour ◽  
Audrey Codran ◽  
Daniel Béchet ◽  
Daniel Taillandier ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Wasting ◽  
Ubiquitin Proteasome System ◽  
Skeletal Muscle Wasting ◽  
Ubiquitin Proteasome

scholarly journals Emerging Strategies Targeting Catabolic Muscle Stress Relief

2020 ◽  
Vol 21 (13) ◽  
pp. 4681 ◽  
Author(s):  
Mattia Scalabrin ◽  
Volker Adams ◽  
Siegfried Labeit ◽  
T. Scott Bowen
Keyword(s):  
Skeletal Muscle ◽  
Muscle Wasting ◽  
Treatment Strategies ◽  
Ring Finger ◽  
Ubiquitin Proteasome System ◽  
Functional Mobility ◽  
Skeletal Muscle Wasting ◽  
Therapeutic Concepts ◽  
Ubiquitin Proteasome

Skeletal muscle wasting represents a common trait in many conditions, including aging, cancer, heart failure, immobilization, and critical illness. Loss of muscle mass leads to impaired functional mobility and severely impedes the quality of life. At present, exercise training remains the only proven treatment for muscle atrophy, yet many patients are too ill, frail, bedridden, or neurologically impaired to perform physical exertion. The development of novel therapeutic strategies that can be applied to an in vivo context and attenuate secondary myopathies represents an unmet medical need. This review discusses recent progress in understanding the molecular pathways involved in regulating skeletal muscle wasting with a focus on pro-catabolic factors, in particular, the ubiquitin-proteasome system and its activating muscle-specific E3 ligase RING-finger protein 1 (MuRF1). Mechanistic progress has provided the opportunity to design experimental therapeutic concepts that may affect the ubiquitin-proteasome system and prevent subsequent muscle wasting, with novel advances made in regards to nutritional supplements, nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) inhibitors, myostatin antibodies, β2 adrenergic agonists, and small-molecules interfering with MuRF1, which all emerge as a novel in vivo treatment strategies for muscle wasting.

The ubiquitin–proteasome system and skeletal muscle wasting

2005 ◽  
Vol 41 ◽  
pp. 173-186 ◽  
Author(s):  
Didier Attaix ◽  
Sophie Ventadour ◽  
Audrey Codran ◽  
Daniel Béchet ◽  
Daniel Taillandier ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Wasting ◽  
Proteolytic Enzymes ◽  
Cathepsin L ◽  
Ubiquitin Proteasome System ◽  
Complete Breakdown ◽  
Skeletal Muscle Proteins ◽  
Ubiquitin Proteasome ◽  
Tripeptidyl Peptidase Ii ◽  
F Box Protein

The ubiquitin–proteasome system (UPS) is believed to degrade the major contractile skeletal muscle proteins and plays a major role in muscle wasting. Different and multiple events in the ubiquitination, deubiquitination and proteolytic machineries are responsible for the activation of the system and subsequent muscle wasting. However, other proteolytic enzymes act upstream (possibly m-calpain, cathepsin L, and/or caspase 3) and downstream (tripeptidyl-peptidase II and aminopeptidases) of the UPS, for the complete breakdown of the myofibrillar proteins into free amino acids. Recent studies have identified a few critical proteins that seem necessary for muscle wasting {i.e. the MAFbx (muscle atrophy F-box protein, also called atrogin-1) and MuRF-1 [muscle-specific RING (really interesting new gene) finger 1] ubiquitin–protein ligases}. The characterization of their signalling pathways is leading to new pharmacological approaches that can be useful to block or partially prevent muscle wasting in human patients.

scholarly journals Walk the Line: The Role of Ubiquitin in Regulating Transcription in Myocytes

Physiology ◽  
2019 ◽  
Vol 34 (5) ◽  
pp. 327-340 ◽  
Author(s):  
Vidyani Suryadevara ◽  
Monte S. Willis
Keyword(s):  
Skeletal Muscle ◽  
Quality Control ◽  
Transcription Factors ◽  
Muscle Wasting ◽  
Protein Quality ◽  
Skeletal Muscle Wasting ◽  
Ubiquitin Proteasome ◽  
Specific Activities ◽  
Novel Targets

The ubiquitin-proteasome offers novel targets for potential therapies with their specific activities and tissue localization. Recently, the expansion of our understanding of how ubiquitin ligases (E3s) specifically regulate transcription has demonstrated their roles in skeletal muscle, complementing their roles in protein quality control and protein degradation. This review focuses on skeletal muscle E3s that regulate transcription factors critical to myogenesis and the maintenance of skeletal muscle wasting diseases.

Myostatin promotes the wasting of human myoblast cultures through promoting ubiquitin-proteasome pathway-mediated loss of sarcomeric proteins

2011 ◽  
Vol 301 (6) ◽  
pp. C1316-C1324 ◽  
Author(s):  
Sudarsanareddy Lokireddy ◽  
Vincent Mouly ◽  
Gillian Butler-Browne ◽  
Peter D. Gluckman ◽  
Mridula Sharma ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Human Skeletal Muscle ◽  
Muscle Wasting ◽  
Negative Regulator ◽  
Potent Inducer ◽  
Ubiquitin Proteasome Pathway ◽  
Skeletal Muscle Wasting ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

Myostatin is a negative regulator of skeletal muscle growth and in fact acts as a potent inducer of “cachectic-like” muscle wasting in mice. The mechanism of action of myostatin in promoting muscle wasting has been predominantly studied in murine models. Despite numerous reports linking elevated levels of myostatin to human skeletal muscle wasting conditions, little is currently known about the signaling mechanism(s) through which myostatin promotes human skeletal muscle wasting. Therefore, in this present study we describe in further detail the mechanisms behind myostatin regulation of human skeletal muscle wasting using an in vitro human primary myotube atrophy model. Treatment of human myotube populations with myostatin promoted dramatic myotubular atrophy. Mechanistically, myostatin-induced myotube atrophy resulted in reduced p-AKT concomitant with the accumulation of active dephosphorylated Forkhead Box-O (FOXO1) and FOXO3. We further show that addition of myostatin results in enhanced activation of atrogin-1 and muscle-specific RING finger protein 1 (MURF1) and reduced expression of both myosin light chain (MYL) and myosin heavy chain (MYH). In addition, we found that myostatin-induced loss of MYL and MYH proteins is dependent on the activity of the proteasome and mediated via SMAD3-dependent regulation of FOXO1 and atrogin-1. Therefore, these data suggest that the mechanism through which myostatin promotes muscle wasting is very well conserved between species, and that myostatin-induced human myotube atrophy is mediated through inhibition of insulin-like growth factor (IGF)/phosphoinositide 3-kinase (PI3-K)/AKT signaling and enhanced activation of the ubiquitin-proteasome pathway and elevated protein degradation.

scholarly journals ER Stress and Unfolded Protein Response in Cancer Cachexia

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1929 ◽  
Author(s):  
Anirban Roy ◽  
Ashok Kumar
Keyword(s):  
Skeletal Muscle ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Ubiquitin Proteasome System ◽  
Unfolded Protein ◽  
Wasting Syndrome ◽  
Skeletal Muscle Wasting ◽  
Protein Response

Cancer cachexia is a devastating syndrome characterized by unintentional weight loss attributed to extensive skeletal muscle wasting. The pathogenesis of cachexia is multifactorial because of complex interactions of tumor and host factors. The irreversible wasting syndrome has been ascribed to systemic inflammation, insulin resistance, dysfunctional mitochondria, oxidative stress, and heightened activation of ubiquitin-proteasome system and macroautophagy. Accumulating evidence suggests that deviant regulation of an array of signaling pathways engenders cancer cachexia where the human body is sustained in an incessant self-consuming catabolic state. Recent studies have further suggested that several components of endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) are activated in skeletal muscle of animal models and muscle biopsies of cachectic cancer patients. However, the exact role of ER stress and the individual arms of the UPR in the regulation of skeletal muscle mass in various catabolic states including cancer has just begun to be elucidated. This review provides a succinct overview of emerging roles of ER stress and the UPR in cancer-induced skeletal muscle wasting.

Fenofibrate, a PPARα agonist, decreases atrogenes and myostatin expression and improves arthritis-induced skeletal muscle atrophy

2011 ◽  
Vol 300 (5) ◽  
pp. E790-E799 ◽  
Author(s):  
Estíbaliz Castillero ◽  
María Paz Nieto-Bona ◽  
Carmen Fernández-Galaz ◽  
Ana Isabel Martín ◽  
María López-Menduiña ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Ubiquitin Proteasome System ◽  
Skeletal Muscle Atrophy ◽  
Skeletal Muscle Wasting ◽  
Cross Section Area ◽  
Section Area ◽  
Ubiquitin Proteasome ◽  
Injection Control

Arthritis is a chronic inflammatory illness that induces cachexia, which has a direct impact on morbidity and mortality. Fenofibrate, a selective PPARα activator prescribed to treat human dyslipidemia, has been reported to decrease inflammation in rheumatoid arthritis patients. The aim of this study was to elucidate whether fenofibrate is able to ameliorate skeletal muscle wasting in adjuvant-induced arthritis, an experimental model of rheumatoid arthritis. On day 4 after adjuvant injection, control and arthritic rats were treated with 300 mg/kg fenofibrate until day 15, when all rats were euthanized. Fenofibrate decreased external signs of arthritis and liver TNFα and blocked arthritis-induced decreased in PPARα expression in the gastrocnemius muscle. Arthritis decreased gastrocnemius weight, which results from a decrease in cross-section area and myofiber size, whereas fenofibrate administration to arthritic rats attenuated the decrease in both gastrocnemius weight and fast myofiber size. Fenofibrate treatment prevented arthritis-induced increase in atrogin-1 and MuRF1 expression in the gastrocnemius. Neither arthritis nor fenofibrate administration modify Akt-FoxO3 signaling. Myostatin expression was not modified by arthritis, but fenofibrate decreased myostatin expression in the gastrocnemius of arthritic rats. Arthritis increased muscle expression of MyoD, PCNA, and myogenin in the rats treated with vehicle but not in those treated with fenofibrate. The results indicate that, in experimental arthritis, fenofibrate decreases skeletal muscle atrophy through inhibition of the ubiquitin-proteasome system and myostatin.

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