A porcine model of acute quadriplegic myopathy: a feasibility study

Norman, Holly S.; Kandala, Krishna; Kolluri, Raghu; Zackrisson, Håkan; Nordquist, Jenny; Walther, Sten; Eriksson, Lars; Larsson, Lars

doi:10.1111/j.1399-6576.2006.01105.x

Cited by 36 publications

(67 citation statements)

References 37 publications

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“…Previously, experiments with the porcine model were typically for shorter durations, i.e., a day or less. In pilot experiments, it was shown that mechanically ventilated pigs exposed to NMB, systemic administration of corticosteroids, and sepsis for 5 days developed an electrophysiological phenotype resembling previous observations in ICU patients with CIM, i.e., reduced compound muscle action potential (CMAP) amplitudes with maintained motor nerve conduction velocity and intact sensory nerve action potential amplitude and conduction velocity (511,517 ) (FIGURE 14C). This model was subsequently used in a series of studies focusing on the relative importance of different trigger agents such as neuromuscular blockade, sepsis, and steroids in the pathogenesis of CIM, muscle specific differences, as well as the effects of a Ca 2ϩ sensitizer on diaphragm muscle fiber function (1,2,32,511,517,520,566,686).…”

Section: Porcine Icu Modelmentioning

confidence: 72%

“…Furthermore, the complete "mechanical silencing," unique for ICU patients, has been shown to play an important role in the development of CIM in experimental and clinical studies (435,517,574). 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).…”

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

confidence: 99%

“…However, experimental porcine models have for many years been used to study the effects of sepsis on organ function (FIGURE 14) (11,522) and in the development, treatment, and testing of diagnostic markers of malignant hyperthermia (476). The porcine model was, therefore, forwarded as an ideal candidate for an animal model of CIM, due to the known similarity in metabolism between humans and pigs and extensive experience with this model (511). In this porcine model, the same type of ventilators used in ICU patients can be used in pigs.…”

Section: Porcine Icu Modelmentioning

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

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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: Porcine Icu Modelmentioning

confidence: 72%

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

confidence: 99%

Section: Porcine Icu Modelmentioning

confidence: 99%

See 1 more Smart Citation

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

Friedrich

Reid

Berghe

et al. 2015

Physiological Reviews

Self Cite

300

329

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“…Myostatin inhibits activation of the Akt/mTOR/ p70S6 protein synthesis pathway, which mediates both differentiation in myoblasts and hypertrophy in myotubes (65). In our previous study using the porcine ICU model, where piglets were exposed to only immobilization and mechanical ventilation for 5 days, activin receptor type-2B (ACVR2B) was downregulated more than twofold, and biceps femoris fiber size and force generating capacity were maintained in these animals (6,47). ACVR2B is associated with myostatin binding/signaling, and its strong impact on skeletal muscle has been confirmed in transgenic mice, where a dominant-negative form of ACVR2B has been shown to cause a significant increase in muscle mass (39).…”

Section: Discussionmentioning

confidence: 99%

“…Reverse transcription and quantitative PCR analysis was performed as previously described (47). Briefly, total RNA (100 ng) was reverse transcribed to cDNA using Qscript cDNA supermix (Quanta Biosciences).…”

Section: Methodsmentioning

confidence: 99%

Mechanisms underlying the sparing of masticatory versus limb muscle function in an experimental critical illness model

Aare

Ochala

Norman

et al. 2011

Physiological Genomics

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-Acute quadriplegic myopathy (AQM) is a common debilitating acquired disorder in critically ill intensive care unit (ICU) patients that is characterized by tetraplegia/generalized weakness of limb and trunk muscles. Masticatory muscles, on the other hand, are typically spared or less affected, yet the mechanisms underlying this striking muscle-specific difference remain unknown. This study aims to evaluate physiological parameters and the gene expression profiles of masticatory and limb muscles exposed to factors suggested to trigger AQM, such as mechanical ventilation, immobilization, neuromuscular blocking agents, corticosteroids (CS), and sepsis for 5 days by using a unique porcine model mimicking the ICU conditions. Single muscle fiber cross-sectional area and force-generating capacity, i.e., maximum force normalized to fiber cross-sectional area (specific force), revealed maintained masseter single muscle fiber cross-sectional area and specific-force after 5 days' exposure to all triggering factors. This is in sharp contrast to observations in limb and trunk muscles, showing a dramatic decline in specific force in response to 5 days' exposure to the triggering factors. Significant differences in gene expression were observed between craniofacial and limb muscles, indicating a highly complex and muscle-specific response involving transcription and growth factors, heat shock proteins, matrix metalloproteinase inhibitor, oxidative stress responsive elements, and sarcomeric proteins underlying the relative sparing of cranial vs. spinal nerve innervated muscles during exposure to the ICU intervention. masseter muscle; myosin; acute quadriplegic myopathy; critical illness myopathy; myostatin; heat-shock protein genes SEVERE MUSCLE WASTING AND impaired muscle function accompany critical illness in intensive care unit (ICU) patients and contribute to the prolonged course of weaning from mechanical ventilation and complicate recovery from primary disease. Some ICU patients develop a more severe and distinct phenotype of generalized paralysis of limb and trunk muscles yet show intact sensory and cognitive functions. This acquired disorder has been given a number of descriptive titles, such as acute quadriplegic myopathy (AQM), critical illness myopathy, thick filament myosin myopathy, acute myopathy in severe asthma, and myopathy of intensive care (34). In AQM, the muscle paralysis and muscle wasting have a primarily myogenic origin and were previously regarded as a rare condition of limited clinical significance. However, it is now established that neuromuscular dysfunction is found in up to 30% of the general ICU population and 70 -80% of certain subgroups of patients display persistent quadriplegia/generalized weakness after a 28-day ICU stay (20,34). Although the mechanisms underlying AQM remain unknown, mechanical ventilation, neuromuscular transmission blockade, systemic administration of corticosteroids (CS), and sepsis have all been proposed as factors triggering this disorder (34, 37).In patients with AQM, c...

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A prospective clinical study on the mechanisms underlying critical illness myopathy—A time‐course approach

Cacciani

Skärlén

Wen

et al. 2022

J cachexia sarcopenia muscle

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Background Critical illness myopathy (CIM) is a consequence of modern critical care resulting in general muscle wasting and paralyses of all limb and trunk muscles, resulting in prolonged weaning from the ventilator, intensive care unit (ICU) treatment and rehabilitation. CIM is associated with severe morbidity/mortality and significant negative socioeconomic consequences, which has become increasingly evident during the current COVID-19 pandemic, but underlying mechanisms remain elusive. Methods Ten neuro-ICU patients exposed to long-term controlled mechanical ventilation were followed with repeated muscle biopsies, electrophysiology and plasma collection three times per week for up to 12 days. Single muscle fibre contractile recordings were conducted on the first and final biopsy, and a multiomics approach was taken to analyse gene and protein expression in muscle and plasma at all collection time points. Results (i) A progressive preferential myosin loss, the hallmark of CIM, was observed in all neuro-ICU patients during the observation period (myosin:actin ratio decreased from 2.0 in the first to 0.9 in the final biopsy, P < 0.001). The myosin loss was coupled to a general transcriptional downregulation of myofibrillar proteins (P < 0.05; absolute fold change >2) and activation of protein degradation pathways (false discovery rate [FDR] <0.1), resulting in significant muscle fibre atrophy and loss in force generation capacity, which declined >65% during the 12 day observation period (muscle fibre cross-sectional area [CSA] and maximum single muscle fibre force normalized to CSA [specific force] declined 30% [P < 0.007] and 50% [P < 0.0001], respectively). (ii) Membrane excitability was not affected as indicated by the maintained compound muscle action potential amplitude upon supramaximal stimulation of upper and lower extremity motor nerves. (iii) Analyses of plasma revealed early activation of inflammatory and proinflammatory pathways (FDR < 0.1), as well as a redistribution of zinc ions from plasma. Conclusions The mechanical ventilation-induced lung injury with release of cytokines/chemokines and the complete mechanical silencing uniquely observed in immobilized ICU patients affecting skeletal muscle gene/protein expression are forwarded as the dominant factors triggering CIM.

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A porcine model of acute quadriplegic myopathy: a feasibility study

Cited by 36 publications

References 37 publications

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

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

Mechanisms underlying the sparing of masticatory versus limb muscle function in an experimental critical illness model

A prospective clinical study on the mechanisms underlying critical illness myopathy—A time‐course approach

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