Muscle atrophy and preferential loss of myosin in prolonged critically ill patients*

Derde, Sarah; Hermans, Greet; Derese, Inge; Güiza, Fabián; Hedström, Yvette; Wouters, Pieter; Bruyninckx, Frans; D’Hoore, André; Larsson, Lars; Berghe, Greet Van den; Vanhorebeek, Ilse

doi:10.1097/ccm.0b013e31822d7c18

Cited by 120 publications

(134 citation statements)

References 12 publications

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“…In fact, the initial studies did not investigate whether autophagy is sufficiently activated to cope with the severe damage inflicted by critical illness. However, a clinical study that considered consequences of insufficient autophagy confirmed similar changes in skeletal muscle and liver of critically ill patients as observed in autophagy-deficient mice (FIGURE 10) (154,728). These included the accumulation of ubiquitin aggregates and other autophagy substrates, such as p62, deformed mitochondria, and aberrant concentric membranous structures.…”

Section: Autophagy In Critical Illnessmentioning

confidence: 98%

“…Interestingly, proteasome activity was also elevated by 30% in serratus anterior, a muscle of the rib cage. In rectus abdomi- nis muscle, a more than twofold increase in chymotrypsinlike activity of the 20S-proteasome has been described (154). Such functional readouts are certainly more informative and preferable over simple transcript or protein content analyses which may not account for the temporary nature of mRNA levels, which can be as short-lived and fall quickly during prolonged muscle proteolysis (409).…”

Section: A the Ubiquitin-proteasome Pathway In Critical Illnessmentioning

confidence: 99%

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The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

Friedrich

Reid

Berghe

et al. 2015

Physiological Reviews

291

329

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Critical illness polyneuropathies (CIP) and myopathies (CIM) are common complications of critical illness. Several weakness syndromes are summarized under the term intensive care unit-acquired weakness (ICUAW). We propose a classification of different ICUAW forms (CIM, CIP, sepsis-induced, steroid-denervation myopathy) and pathophysiological mechanisms from clinical and animal model data. Triggers include sepsis, mechanical ventilation, muscle unloading, steroid treatment, or denervation. Some ICUAW forms require stringent diagnostic features; CIM is marked by membrane hypoexcitability, severe atrophy, preferential myosin loss, ultrastructural alterations, and inadequate autophagy activation while myopathies in pure sepsis do not reproduce marked myosin loss. Reduced membrane excitability results from depolarization and ion channel dysfunction. Mitochondrial dysfunction contributes to energy-dependent processes. Ubiquitin proteasome and calpain activation trigger muscle proteolysis and atrophy while protein synthesis is impaired. Myosin loss is more pronounced than actin loss in CIM. Protein quality control is altered by inadequate autophagy. Ca 2ϩ dysregulation is present through altered Ca 2ϩ homeostasis. We highlight clinical hallmarks, trigger factors, and potential mechanisms from human studies and animal models that allow separation of risk factors that may trigger distinct mechanisms contributing to weakness. During critical illness, altered inflammatory (cytokines) and metabolic pathways deteriorate muscle function. ICUAW prevention/treatment is limited, e.g., tight glycemic control, delaying nutrition, and early mobilization. Future challenges include identification of primary/secondary events during the time course of critical illness, the interplay between membrane excitability, bioenergetic failure and differential proteolysis, and finding new therapeutic targets by help of tailored animal models.

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Section: Autophagy In Critical Illnessmentioning

confidence: 98%

Section: A the Ubiquitin-proteasome Pathway In Critical Illnessmentioning

confidence: 99%

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

Friedrich

Reid

Berghe

et al. 2015

Physiological Reviews

291

329

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“…Therefore, our finding that MS-275 completely prevented the decrease in specific force in 10-dayimmobilized muscles suggests that class I HDACs contribute to contractile dysfunction during disuse. There are several potential mechanisms that might contribute to contractile dysfunction during muscle disuse, including (but not limited to) shifts in myosin isoforms (Caiozzo et al, 1998;Caiozzo et al, 1996;Campione et al, 1993;Fitts et al, 2000), alterations in Ca 2+ release and sensitivity (Fraysse et al, 2003), and the preferential degradation of myosin heavy chain (MHC) (Derde et al, 2012;Ochala et al, 2011), which is mediated through the FoxO target gene MuRF1 . Because we found that HDAC1 was necessary for both activation of FoxO and the expression of MuRF1, and MS-275 preferentially inhibits HDAC1, we hypothesized that the preservation of specific force might be related to the sparing of MHC.…”

Section: Inhibition Of Class I Hdacs During Skeletal Muscle Disuse Prmentioning

confidence: 99%

HDAC1 activates FoxO and is both sufficient and required for skeletal muscle atrophy

Beharry

Sandesara

Roberts

et al. 2014

Journal of Cell Science

102

116

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The Forkhead box O (FoxO) transcription factors are activated, and necessary for the muscle atrophy, in several pathophysiological conditions, including muscle disuse and cancer cachexia. However, the mechanisms that lead to FoxO activation are not well defined. Recent data from our laboratory and others indicate that the activity of FoxO is repressed under basal conditions via reversible lysine acetylation, which becomes compromised during catabolic conditions. Therefore, we aimed to determine how histone deacetylase (HDAC) proteins contribute to activation of FoxO and induction of the muscle atrophy program. Through the use of various pharmacological inhibitors to block HDAC activity, we demonstrate that class I HDACs are key regulators of FoxO and the muscle-atrophy program during both nutrient deprivation and skeletal muscle disuse. Furthermore, we demonstrate, through the use of wild-type and dominant-negative HDAC1 expression plasmids, that HDAC1 is sufficient to activate FoxO and induce muscle fiber atrophy in vivo and is necessary for the atrophy of muscle fibers that is associated with muscle disuse. The ability of HDAC1 to cause muscle atrophy required its deacetylase activity and was linked to the induction of several atrophy genes by HDAC1, including atrogin-1, which required deacetylation of FoxO3a. Moreover, pharmacological inhibition of class I HDACs during muscle disuse, using MS-275, significantly attenuated both disuse muscle fiber atrophy and contractile dysfunction. Together, these data solidify the importance of class I HDACs in the muscle atrophy program and indicate that class I HDAC inhibitors are feasible countermeasures to impede muscle atrophy and weakness.

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“…On the other hand, Derde et al [110], using muscle biopsy samples, demonstrated that IIT does not affect myofiber size, myofibrillar protein synthesis ability, or muscle proteolytic markers. ITT is considered to primarily have a neuroprotective role [107], but no neurological data are available.…”

Section: Intensive Insulin Treatmentmentioning

confidence: 99%

Skeletal Muscle Dysfunction in Critical Illness

Iida¹,

Sakuma²

2017

Physical Disabilities - Therapeutic Implications

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Despite improvements in critical illness survival rates with recent developments in medical care, many patients still have long-term physical disabilities following stays in the intensive care unit (ICU). Critical illness-induced muscle weakness, so-called ICU-acquired weakness (ICU-AW), is a common occurrence in approximately 50% of critically ill patients in the ICU requiring mechanical ventilation for >7 days. ICU-AW contributes to increases in duration of mechanical ventilation and lengths of ICU and hospital stays and may persist among survivors for several years after discharge. Risk factors for ICU-AW include systemic inflammatory responses, severe sepsis, muscle inactivity, hyperglycemia, and use of neuromuscular blockers. Thus, the development of muscle wasting is suggested to be associated with pathophysiological alterations leading to an imbalance between muscle proteolysis and proteosynthesis through several cellular signaling networks. This chapter presents a review of the literature regarding critical illness-induced muscle wasting and describes potential treatment of excessive muscle catabolism.

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Muscle atrophy and preferential loss of myosin in prolonged critically ill patients*

Cited by 120 publications

References 12 publications

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

HDAC1 activates FoxO and is both sufficient and required for skeletal muscle atrophy

Skeletal Muscle Dysfunction in Critical Illness

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