Title efficacy of phosphodiesterase 5 inhibitor on distant burn-induced muscle autophagy, microcirculation, and survival rate

Skeletal muscle wasting is an exacerbating factor in the prognosis of critically ill patients. Using a systemic burn injury model in mice, we have established a role of autophagy in the resulting muscle wasting that is distant from the burn trauma. We provide evidence that burn injury increases the autophagy turnover in the distal skeletal muscle by conventional postmortem tissue analyses and by a novel in vivo microscopic method using an autophagy reporter gene (tandem fluorescent LC3). The effect of tadalafil, a phosphodiesterase 5 inhibitor (PDE5I), on burn-induced skeletal muscle autophagy is documented and extends our published results that PDE5Is attenuates muscle degeneration in a muscular dystrophy model. We also designed a translational experiment to examine the impact of PDE5I on whole body and demonstrated that PDE5I administration lessened muscle atrophy, mitigated microcirculatory disturbance, and improved the survival rate after burn injury.

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In vivo rabbit hindquarter model for assessment of regional burn hypermetabolism

Journal of Applied Physiology ◽

10.1152/japplphysiol.00513.2002 ◽

2003 ◽

Vol 94 (1) ◽

pp. 135-140 ◽

Cited By ~ 4

Author(s):

Ji Xu ◽

Zhewei Fei ◽

Yong-Ming Yu ◽

Wenyin Xu ◽

Andrew Rhodes ◽

...

Keyword(s):

Muscle Wasting ◽

Burn Injury ◽

Statistical Significance ◽

Resting Energy Expenditure ◽

Whole Body ◽

Constant Infusion ◽

Severe Burn ◽

Vascular Catheters ◽

Induced Changes

Severe burn injury evokes hypermetabolism and muscle wasting, despite nominally adequate nutrition. Although there is much information on whole organism and isolated tissue metabolism after burn injury, data examining regional burn hypermetabolism in vivo are lacking. Using surgically implanted (general anesthesia) regional vascular catheters and primed constant infusion of l-[1-13C]phenylalanine tracer, we have determined in vivo burn-induced alterations in rabbit hindquarter protein and energy metabolism. Burn injury evokes increased whole body resting energy expenditure and phenylalanine turnover, accompanied by significantly increased hindquarter proteolysis, creating a negative protein balance in burned rabbit hindquarter. Hindquarter oxygen consumption showed an increase after burn injury, but it did not reach statistical significance. Burn-induced changes in hindquarter protein turnover account for approximately one-third of the whole animal hypermetabolism. This model offers a system for regional manipulation of postburn hypermetabolism.

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Emerging Strategies Targeting Catabolic Muscle Stress Relief

International Journal of Molecular Sciences ◽

10.3390/ijms21134681 ◽

2020 ◽

Vol 21 (13) ◽

pp. 4681 ◽

Cited By ~ 1

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.

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ER stress and subsequent activated calpain play a pivotal role in skeletal muscle wasting after severe burn injury

PLoS ONE ◽

10.1371/journal.pone.0186128 ◽

2017 ◽

Vol 12 (10) ◽

pp. e0186128 ◽

Cited By ~ 15

Author(s):

Li Ma ◽

Wanli Chu ◽

Jiake Chai ◽

Chuanan Shen ◽

Dawei Li ◽

...

Keyword(s):

Skeletal Muscle ◽

Er Stress ◽

Muscle Wasting ◽

Burn Injury ◽

Pivotal Role ◽

Severe Burn ◽

Skeletal Muscle Wasting ◽

Severe Burn Injury

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Role of autophagy in sepsis-induced skeletal muscle dysfunction, whole-body metabolism, and survival

10.1101/2021.08.05.455081 ◽

2021 ◽

Author(s):

Jean-Philippe Leduc-Gaudet ◽

Kayla Miguez ◽

Marina Cefis ◽

Alaa Moamer ◽

Tomer Jordi Chaffer ◽

...

Keyword(s):

Skeletal Muscle ◽

Mitochondrial Dysfunction ◽

Skeletal Muscles ◽

Muscle Wasting ◽

26S Proteasome ◽

Whole Body ◽

Protective Mechanism ◽

Muscle Dysfunction ◽

Sham Operation ◽

The Impact

Septic patients frequently develop skeletal muscle wasting and weakness, resulting in severe clinical consequences and adverse outcomes. Autophagy is a stress-induced degradative process essential to cell survival. Recent studies have demonstrated that sepsis triggers sustained induction of autophagy in skeletal muscles, although the impact of this enhanced autophagy on sepsis-induced muscle dysfunction remains unclear. Atg7 is an autophagy gene that plays a major role in autophagosome formation. Using an inducible and muscle-specific Atg7 knockout mouse model (Atg7iSkM-KO), we investigated the functional importance of skeletal muscle autophagy in sepsis. Sepsis was induced using cecal ligation and perforation (CLP) with a sham operation serving as a control. Atg7iSkM-KO mice exhibited a more severe phenotype in response to sepsis, marked by severe muscle wasting and contractile dysfunction, hypoglycemia, higher ketone levels and a decreased in survival as compared to mice with intact Atg7. Several genes that encode 26S proteasome subunits were upregulated, suggesting that activation of the ubiquitin-proteasome system is responsible for the severe muscle atrophy that was seen in these mice. Sepsis and Atg7 deletion resulted in the accumulation of mitochondrial dysfunction, although sepsis did not further worsen mitochondrial dysfunction in Atg7iSkM-KO mice. Overall, our study demonstrates that autophagy inactivation in skeletal muscles triggers significant worsening of sepsis-induced contractile and metabolic dysfunctions and negatively impacts survival. Induction of autophagy in skeletal muscles in response to sepsis thus represents a protective mechanism.

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The impact of skeletal muscle wasting during neoadjuvant chemotherapy on postoperative anastomotic leakage in patients with esophageal cancer

Esophagus ◽

10.1007/s10388-020-00774-1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Shiro Fujihata ◽

Ryo Ogawa ◽

Seiichi Nakaya ◽

Shunsuke Hayakawa ◽

Tomotaka Okubo ◽

...

Keyword(s):

Skeletal Muscle ◽

Esophageal Cancer ◽

Neoadjuvant Chemotherapy ◽

Anastomotic Leakage ◽

Muscle Wasting ◽

Skeletal Muscle Wasting ◽

The Impact

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

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00146.2010 ◽

2010 ◽

Vol 298 (5) ◽

pp. H1565-H1570 ◽

Cited By ~ 72

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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The Role of Systemic Inflammation in Cancer-Associated Muscle Wasting and Rationale for Exercise as a Therapeutic Intervention

JCSM Clinical Reports ◽

10.17987/jcsm-cr.v3i2.65 ◽

2018 ◽

Vol 3 (2) ◽

Cited By ~ 4

Author(s):

Calvin Lloyd Cole ◽

Ian R. Kleckner ◽

Aminah Jatoi ◽

Edward Schwarz ◽

Richard F. Dunne

Keyword(s):

Skeletal Muscle ◽

Systemic Inflammation ◽

Cancer Cachexia ◽

Muscle Wasting ◽

Activin A ◽

Therapeutic Interventions ◽

Muscle Quality ◽

Patients With Cancer ◽

Skeletal Muscle Wasting ◽

The Impact

Progressive skeletal muscle wasting in cancer cachexia involves a process of dysregulated protein synthesis and breakdown. This catabolism may be the result of mal-nutrition, and an upregulation of both pro-inflammatory cytokines and the ubiquitin proteasome pathway (UPP), which can subsequently increase myostatin and activin A release. The skeletal muscle wasting associated with cancer cachexia is clinically significant, it can contribute to treatment toxicity or the premature discontinuation of treatments resulting in increases in morbidity and mortality. Thus, there is a need for further investigation into the pathophysiology of muscle wasting in cancer cachexia to develop effective prophylactic and therapeutic interventions. Several studies have identified a central role for chronic-systemic inflammation in initiating and perpetuating muscle wasting in patients with cancer. Interestingly, while exercise has shown efficacy in improving muscle quality, only recently have investigators begun to assess the impact that exercise has on chronic-systemic inflammation. To put this new information into context with established paradigms, here we review several biological pathways (e.g. dysfunctional inflammatory response, hypothalamus pituitary adrenal axis, and increased myostatin/activin A activity) that may be responsible for the muscle wasting in patients with cancer. Additionally, we discuss the potential impact that exercise has on these pathways in the treatment of cancer cachexia. Exercise is an attractive intervention for muscle wasting in this population, partially because it disrupts chronic-systemic inflammation mediated catabolism. Most importantly, exercise is a potent stimulator of muscle synthesis, and therefore this therapy may reverse muscle damage caused by cancer cachexia.

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Suppression of mTORC1 activation in acid-α-glucosidase-deficient cells and mice is ameliorated by leucine supplementation

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00212.2014 ◽

2014 ◽

Vol 307 (10) ◽

pp. R1251-R1259 ◽

Cited By ~ 7

Author(s):

Adi Shemesh ◽

Yichen Wang ◽

Yingjuan Yang ◽

Gong-She Yang ◽

Danielle E. Johnson ◽

...

Keyword(s):

Skeletal Muscle ◽

Pompe Disease ◽

Muscle Wasting ◽

Muscle Protein ◽

Leucine Supplementation ◽

Glycogen Accumulation ◽

Skeletal Muscle Dysfunction ◽

Skeletal Muscle Wasting ◽

Mtorc1 Activation

Pompe disease is due to a deficiency in acid-α-glucosidase (GAA) and results in debilitating skeletal muscle wasting, characterized by the accumulation of glycogen and autophagic vesicles. Given the role of lysosomes as a platform for mTORC1 activation, we examined mTORC1 activity in models of Pompe disease. GAA-knockdown C2C12 myoblasts and GAA-deficient human skin fibroblasts of infantile Pompe patients were found to have decreased mTORC1 activation. Treatment with the cell-permeable leucine analog l-leucyl-l-leucine methyl ester restored mTORC1 activation. In vivo, Pompe mice also displayed reduced basal and leucine-stimulated mTORC1 activation in skeletal muscle, whereas treatment with a combination of insulin and leucine normalized mTORC1 activation. Chronic leucine feeding restored basal and leucine-stimulated mTORC1 activation, while partially protecting Pompe mice from developing kyphosis and the decline in muscle mass. Leucine-treated Pompe mice showed increased spontaneous activity and running capacity, with reduced muscle protein breakdown and glycogen accumulation. Together, these data demonstrate that GAA deficiency results in reduced mTORC1 activation that is partly responsible for the skeletal muscle wasting phenotype. Moreover, mTORC1 stimulation by dietary leucine supplementation prevented some of the detrimental skeletal muscle dysfunction that occurs in the Pompe disease mouse model.

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