Myofibrillar protein and gene expression in acute quadriplegic myopathy

Norman, Holly S.; Zackrisson, Håkan; Hedström, Yvette; Andersson, P.; Nordquist, Jenny; Eriksson, Lars; Libelius, Rolf; Larsson, Lars

doi:10.1016/j.jns.2009.04.041

Cited by 33 publications

(46 citation statements)

References 69 publications

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“…An additional factor that needs to be taken into account is the relatively long delay between exposure to trigger factors and the phenotype characterizing CIM, i.e., severe muscle wasting and preferential myosin loss (399,511,610). The preferential and significant myosin loss is the result of both a decreased synthesis at the transcriptional level and increased myofibrillar protein degradation (399,434,496,513,517). Thus early effects via specific signaling pathways on protein synthesis and degradation become manifest relatively late at the myofibrillar protein level, i.e., the preferential myosin loss, due to the slow turnover rate of contractile proteins with myosin having a 1-2% turnover rate per day (647).…”

Section: A the Problem Of Choosing The Right Animal Model: Matching mentioning

confidence: 99%

“…On the other hand, actin has been reported to have a turnover rate twice as slow as myosin (457). Differences in myosin and actin turnover rates and the preferential targeting of myosin by the E3 ligase MuRF1 for ubiquitination and degradation (127) offer a mechanism underlying the preferential myosin loss in spite of a similar transcriptional downregulation of myosin and actin (513,517). However, there is reason to believe that the mechanism underlying the preferential myosin loss is more complex, involving other mechanisms such as compromised protection by, e.g., small and large heat shock proteins.…”

Section: A the Problem Of Choosing The Right Animal Model: Matching mentioning

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

300

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: A the Problem Of Choosing The Right Animal Model: Matching mentioning

confidence: 99%

Section: A the Problem Of Choosing The Right Animal Model: Matching mentioning

confidence: 99%

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

Friedrich

Reid

Berghe

et al. 2015

Physiological Reviews

300

329

View full text Add to dashboard Cite

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“…Clinically apparent weakness is present in 20-50% of patients with critical illness and has been shown to be an independent risk factor for mortality in these patients (3,5,7,8). A variety of terms have been used in the literature to describe the myopathic weakness in these patients including acute quadriplegic myopathy, critical illness myopathy, and thick filament myopathy, the latter referring to the preferential loss of myosin observed in the muscles of these patients (9)(10)(11).…”

mentioning

confidence: 99%

A Critical Role for Muscle Ring Finger-1 in Acute Lung Injury–associated Skeletal Muscle Wasting

Files

D’Alessio²,

Johnston³

et al. 2012

Am J Respir Crit Care Med

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Rationale: Acute lung injury (ALI) is a debilitating condition associated with severe skeletal muscle weakness that persists in humans long after lung injury has resolved. The molecular mechanisms underlying this condition are unknown. Objectives: To identify the muscle-specific molecular mechanisms responsible for muscle wasting in a mouse model of ALI. Methods: Changes in skeletal muscle weight, fiber size, in vivo contractile performance, and expression of mRNAs and proteins encoding muscle atrophy-associated genes for muscle ring finger-1 (MuRF1) and atrogin1 were measured. Genetic inactivation of MuRF1 or electroporationmediated transduction of miRNA-based short hairpin RNAs targeting either MuRF1 or atrogin1 were used to identify their role in ALIassociated skeletal muscle wasting. Measurements and Main Results: Mice with ALI developed profound muscle atrophy and preferential loss of muscle contractile proteins associated with reduced muscle function in vivo. Although mRNA expression of the muscle-specific ubiquitin ligases, MuRF1 and atrogin1, was increased in ALI mice, only MuRF1 protein levels were up-regulated. Consistent with these changes, suppression of MuRF1 by genetic or biochemical approaches prevented muscle fiber atrophy, whereas suppression of atrogin1 expression was without effect. Despite resolution of lung injury and down-regulation of MuRF1 and atrogin1, force generation in ALI mice remained suppressed. Conclusions: These data show that MuRF1 is responsible for mediating muscle atrophy that occurs during the period of active lung injury in ALI mice and that, as in humans, skeletal muscle dysfunction persists despite resolution of lung injury.Keywords: skeletal muscle atrophy; intensive care unit-acquired weakness; critical illness myopathy; muscle atrophy genes; proteasomal-mediated protein degradation Acute lung injury (ALI) is a syndrome characterized by the acute onset of pulmonary infiltrates and respiratory failure often leading to the need for mechanical ventilation (1). Approximately 200,000 people per year develop ALI in the United States, with mortality high at 30-40% (2). A common complication associated with ALI is skeletal muscle weakness. Weakness in these patients results in decreased long-term mobility and functional status. Skeletal muscle weakness is initiated early in the course of ALI, and has been shown to persist in a large percentage of patients for up to 5 years after resolution of lung injury and hospital discharge (3-6). Although multiple factors may contribute to ALI-induced muscle atrophy including reduced nutrition, inactivity caused by bed rest, and systemic inflammation, the etiology of ALI-associated skeletal muscle atrophy remains incompletely understood.Skeletal muscle weakness is a common finding not only among patients with ALI, but also in patients with other critical illnesses. Clinically apparent weakness is present in 20-50% of patients with critical illness and has been shown to be an independent risk factor for mortality in these patients (3,5,7,8)....

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“…For myosin/␣-actin blots, the myosin signal in each lane was normalized to the ␣-actin in that lane since previous work has shown selective loss of myosin relative to ␣-actin in CIM (43). For all blots, the average of the signal in the control muscle was set at 100%, and Fig.…”

Section: Methodsmentioning

confidence: 99%

“…These include selective loss of myosin (10,30,31,40,43,44,53), disorganization of sarcomeres (10,53), dramatic muscle atrophy (28), and electrical inexcitability of muscle (46,49). All of these features occur in the steroid denervation rat model of the disease (38,40,48,50).…”

mentioning

confidence: 99%

Upregulation of the Ca_V1.1-ryanodine receptor complex in a rat model of critical illness myopathy

Kraner

Wang

Novak

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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The processes that trigger severe muscle atrophy and loss of myosin in critical illness myopathy (CIM) are poorly understood. It has been reported that muscle disuse alters Ca2+ handling by the sarcoplasmic reticulum. Since inactivity is an important contributor to CIM, this finding raises the possibility that elevated levels of the proteins involved in Ca2+ handling might contribute to development of CIM. CIM was induced in 3- to 5-mo-old rats by sciatic nerve lesion and infusion of dexamethasone for 1 wk. Western blot analysis revealed increased levels of ryanodine receptor (RYR) isoforms-1 and -2 as well as the dihydropyridine receptor/voltage-gated calcium channel type 1.1 (DHPR/CaV 1.1). Immunostaining revealed a subset of fibers with elevation of RYR1 and CaV 1.1 that had severe atrophy and disorganization of sarcomeres. These findings suggest increased Ca2+ release from the sarcoplasmic reticulum may be an important contributor to development of CIM. To assess the endogenous functional effects of increased intracellular Ca2+ in CIM, proteolysis of α-fodrin, a well-known target substrate of Ca2+-activated proteases, was measured and found to be 50% greater in CIM. There was also selective degradation of myosin heavy chain relative to actin in CIM muscle. Taken together, our findings suggest that increased Ca2+ release from the sarcoplasmic reticulum may contribute to pathology in CIM.

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Myofibrillar protein and gene expression in acute quadriplegic myopathy

Cited by 33 publications

References 69 publications

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

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

A Critical Role for Muscle Ring Finger-1 in Acute Lung Injury–associated Skeletal Muscle Wasting

Upregulation of the Ca_V1.1-ryanodine receptor complex in a rat model of critical illness myopathy

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Myofibrillar protein and gene expression in acute quadriplegic myopathy

Cited by 33 publications

References 69 publications

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

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

A Critical Role for Muscle Ring Finger-1 in Acute Lung Injury–associated Skeletal Muscle Wasting

Upregulation of the CaV1.1-ryanodine receptor complex in a rat model of critical illness myopathy

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Product

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Upregulation of the Ca_V1.1-ryanodine receptor complex in a rat model of critical illness myopathy