scholarly journals Protein phosphatase 2C-alpha knockdown reduces angiotensin II-mediated skeletal muscle wasting via restoration of mitochondrial recycling and function

2014 ◽  
Vol 4 (1) ◽  
pp. 20 ◽  
Author(s):  
Alexander Tabony ◽  
Tadashi Yoshida ◽  
Sergiy Sukhanov ◽  
Patrice Delafontaine
Keyword(s):  
Skeletal Muscle ◽  
Angiotensin Ii ◽  
Protein Phosphatase ◽  
Muscle Wasting ◽  
Protein Phosphatase 2C ◽  
Skeletal Muscle Wasting ◽  
And Function

scholarly journals Angiotensin II suppresses autophagy and disrupts ultrastructural morphology and function of mitochondria in mouse skeletal muscle

2019 ◽  
Vol 126 (6) ◽  
pp. 1550-1562 ◽  
Author(s):  
Kleiton Augusto Santos Silva ◽  
Thaysa Ghiarone ◽  
Kathy Schreiber ◽  
DeAna Grant ◽  
Tommi White ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Angiotensin Ii ◽  
Protein Expression ◽  
Chronic Diseases ◽  
Muscle Wasting ◽  
Beclin 1 ◽  
Ang Ii ◽  
Autophagosome Formation ◽  
Skeletal Muscle Wasting ◽  
And Function

Angiotensin II (ANG II)-induced skeletal muscle wasting is characterized by activation of the ubiquitin-proteasome system. However, the potential involvement of proteolytic system macroautophagy/autophagy in this wasting process remains elusive. Autophagy is precisely regulated to maintain cell survival and homeostasis; thus its dysregulation (i.e., overactivation or persistent suppression) could lead to detrimental outcomes in skeletal muscle. Here we show that infusion of ANG II for 7 days in male FVB mice suppressed autophagy in skeletal muscle. ANG II blunted microtubule-associated protein 1 light chain 3B (LC3B)-I-to-LC3B-II conversion (an autophagosome marker), increased p62/SQSTM1 (an autophagy cargo receptor) protein expression, and decreased the number of autophagic vacuoles. ANG II inhibited UNC-51-like kinase 1 via inhibition of 5′-AMP-activated kinase and activation of mechanistic target of rapamycin complex 1, leading to reduced phosphorylation of beclin-1Ser14 and Autophagy-related protein 14Ser29, suggesting that ANG II impairs autophagosome formation in skeletal muscle. In line with ANG II-mediated suppression of autophagy, ANG II promoted accumulation of abnormal/damaged mitochondria, characterized by swelling and disorganized cristae and matrix dissolution, with associated increase in PTEN-induced kinase 1 protein expression. ANG II also reduced mitochondrial respiration, indicative of mitochondrial dysfunction. Together, these results demonstrate that ANG II reduces autophagic activity and disrupts mitochondrial ultrastructure and function, likely contributing to skeletal muscle wasting. Therefore, strategies that activate autophagy in skeletal muscle have the potential to prevent or blunt ANG II-induced skeletal muscle wasting in chronic diseases. NEW & NOTEWORTHY Our study identified a novel mechanism whereby angiotensin II (ANG II) impairs mitochondrial energy metabolism in skeletal muscle. ANG II suppressed autophagosome formation by inhibiting the UNC-51-like kinase 1(ULK1)-beclin-1 axis, resulting in accumulation of abnormal/damaged and dysfunctional mitochondria and reduced mitochondrial respiratory capacity. Therapeutic strategies that activate the ULK1-beclin-1 axis have the potential to delay or reverse skeletal muscle wasting in chronic diseases characterized by increased systemic ANG II levels.

scholarly journals HDAC6 contributes to pathological responses of heart and skeletal muscle to chronic angiotensin-II signaling

2014 ◽  
Vol 307 (2) ◽  
pp. H252-H258 ◽  
Author(s):  
Kimberly M. Demos-Davies ◽  
Bradley S. Ferguson ◽  
Maria A. Cavasin ◽  
Jennifer H. Mahaffey ◽  
Sarah M. Williams ◽  
...  
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Angiotensin Ii ◽  
Muscle Wasting ◽  
Striated Muscle ◽  
Systolic Function ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Ang Ii ◽  
Skeletal Muscle Wasting

Little is known about the function of the cytoplasmic histone deacetylase HDAC6 in striated muscle. Here, we addressed the role of HDAC6 in cardiac and skeletal muscle remodeling induced by the peptide hormone angiotensin II (ANG II), which plays a central role in blood pressure control, heart failure, and associated skeletal muscle wasting. Comparable with wild-type (WT) mice, HDAC6 null mice developed cardiac hypertrophy and fibrosis in response to ANG II. However, whereas WT mice developed systolic dysfunction upon treatment with ANG II, cardiac function was maintained in HDAC6 null mice treated with ANG II for up to 8 wk. The cardioprotective effect of HDAC6 deletion was mimicked in WT mice treated with the small molecule HDAC6 inhibitor tubastatin A. HDAC6 null mice also exhibited improved left ventricular function in the setting of pressure overload mediated by transverse aortic constriction. HDAC6 inhibition appeared to preserve systolic function, in part, by enhancing cooperativity of myofibrillar force generation. Finally, we show that HDAC6 null mice are resistant to skeletal muscle wasting mediated by chronic ANG-II signaling. These findings define novel roles for HDAC6 in striated muscle and suggest potential for HDAC6-selective inhibitors for the treatment of cardiac dysfunction and muscle wasting in patients with heart failure.

scholarly journals Skeletal Muscle Wasting and Function Impairment in Intensive Care Patients With Severe COVID-19

2021 ◽  
Vol 12 ◽  
Author(s):  
Mario Chueire de Andrade-Junior ◽  
Isabel Chateaubriand Diniz de Salles ◽  
Christina May Moran de Brito ◽  
Laerte Pastore-Junior ◽  
Renato Fraga Righetti ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Intensive Care ◽  
Muscle Strength ◽  
Muscle Wasting ◽  
Rectus Femoris ◽  
Quadriceps Muscle ◽  
Anterior Compartment ◽  
Intensive Care Patients ◽  
Skeletal Muscle Wasting ◽  
And Function

Background: Intensive care patients commonly develop muscle wasting and functional impairment. However, the role of severe COVID-19 in the magnitude of muscle wasting and functionality in the acute critical disease is unknown.Objective: To perform a prospective characterization to evaluate the skeletal muscle mass and functional performance in intensive care patients with severe COVID-19.Methods: Thirty-two critically ill patients (93.8% male; age: 64.1 ± 12.6 years) with the diagnosis of the severe COVID-19 were prospectively recruited within 24 to 72 h following intensive care unit (ICU) admission, from April 2020 to October 2020, at Hospital Sírio-Libanês in Brazil. Patients were recruited if older than 18 years old, diagnosis of severe COVID-19 confirmed by RT-PCR, ICU stay and absence of limb amputation. Muscle wasting was determined through an ultrasound measurement of the rectus femoris cross-sectional area, the thickness of the anterior compartment of the quadriceps muscle (rectus femoris and vastus intermedius), and echogenicity. The peripheral muscle strength was assessed with a handgrip test. The functionality parameter was determined through the ICU mobility scale (IMS) and the International Classification of Functioning, Disability and Health (ICF). All evaluations were performed on days 1 and 10.Results: There were significant reductions in the rectus femoris cross-section area (−30.1% [95% IC, −26.0% to −34.1%]; P < 0.05), thickness of the anterior compartment of the quadriceps muscle (−18.6% [95% IC, −14.6% to 22.5%]; P < 0.05) and handgrip strength (−22.3% [95% IC, 4.7% to 39.9%]; P < 0.05) from days 1 to 10. Patients showed increased mobility (0 [0–5] vs 4.5 [0–8]; P < 0.05), improvement in respiratory function (3 [3–3] vs 2 [1–3]; P < 0.05) and structure respiratory system (3 [3–3] vs 2 [1–3]; P < 0.05), but none of the patients returned to normal levels.Conclusion: In intensive care patients with severe COVID-19, muscle wasting and decreased muscle strength occurred early and rapidly during 10 days of ICU stay with improved mobility and respiratory functions, although they remained below normal levels. These findings may provide insights into skeletal muscle wasting and function in patients with severe COVID-19.

Abstract 13433: Angiotensin II Type 2 Receptor Regulates Skeletal Myoblast Differentiation: Implications for treatment of Cachexia and Skeletal Muscle Wasting

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Tadashi Yoshida ◽  
Patrice Delafontaine
Keyword(s):  
Skeletal Muscle ◽  
Angiotensin Ii ◽  
Muscle Regeneration ◽  
Muscle Wasting ◽  
Skeletal Muscle Regeneration ◽  
Myoblast Differentiation ◽  
Muscle Physiology ◽  
Ang Ii ◽  
Skeletal Muscle Wasting

Patients with advanced congestive heart failure (CHF) or chronic kidney disease (CKD) often have increased angiotensin II (Ang II) levels and cachexia. We previously demonstrated that Ang II infusion in rodents causes skeletal muscle wasting and decreases muscle regenerative potential via Ang II type 1 receptor (AT1R) signaling, likely contributing to cachexia in CHF and CKD. However, the potential role of Ang II type 2 receptor (AT2R) signaling in skeletal muscle physiology remains unknown. We found that AT2R expression was robustly increased in mouse skeletal myoblasts during differentiation, suggesting that the AT2R plays an important role in skeletal muscle regeneration. To test this hypothesis, we infused mice with AT2R antagonist PD123319 (PD, 30 mg/kg/d) or agonist CGP123319 (CGP, 1 μg/kg/min) during cardiotoxin (CTX)-induced muscle injury and regeneration. PD reduced the size of regenerating myofibers (727.5±54.6 and 516.0±37.0 μm2 in sham and PD, respectively, p<0.05) and expression of the myoblast differentiation markers myogenin and eMyHC (56.9% and 40.2% decrease in PD, respectively. p<0.01), whereas CGP had the opposite effects. siRNA mediated AT2R knockdown in mouse primary myoblasts suppressed the increase of myogenin and desmin, resulting in lowered differentiation. We analyzed changes in phosphoprotein levels in myoblasts after AT2R knockdown by phosphoprotein array and identified multiple changes, including increased phospho-ERK1/2 levels. Importantly, inhibition of ERK1/2 restored normal myoblast differentiation in the setting of AT2R knockdown, suggesting the AT2R positively regulates myoblast differentiation by reducing ERK1/2 activity. Furthermore, we found that skeletal muscle regeneration was reduced (decreased regenerating myofiber size and myogenin/desmin expression) in a mouse myocardial infarction model of CHF, concomitantly with markedly blunted increase of AT2R expression, strongly suggesting that the AT2R plays an important role in the reduction of skeletal muscle function in CHF. These data indicate that AT2R signaling positively regulates myoblast differentiation and potentiates skeletal muscle regeneration, providing a new therapeutic target in wasting disorders such as CHF and CKD.

scholarly journals Angiotensin II Induces Skeletal Muscle Wasting through Enhanced Protein Degradation and Down-Regulates Autocrine Insulin-Like Growth Factor I*

Endocrinology ◽  
2001 ◽  
Vol 142 (4) ◽  
pp. 1489-1496 ◽  
Author(s):  
Marijke Brink ◽  
S. Russ Price ◽  
Jacqueline Chrast ◽  
James L. Bailey ◽  
Asif Anwar ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Angiotensin Ii ◽  
Growth Factor ◽  
Protein Degradation ◽  
Muscle Wasting ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Skeletal Muscle Wasting ◽  
Growth Factor I
Sign in / Sign up

Export Citation Format

Share Document