Muscle wasting and the temporal gene expression pattern in a novel rat intensive care unit model

Llano‐Diez, Monica; Gustafson, Ann-Marie; Olsson, Carl A.; Göransson, Hanna; Larsson, Lars

doi:10.1186/1471-2164-12-602

Cited by 64 publications

(72 citation statements)

References 68 publications

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“…These genes-together with Fboxo32 (Mafbx), because of its previously defined role with Trim63 (Murf1) in muscle atrophy-were then analyzed via real-time qRT-PCR to confirm microarray gene expression data for these genes as well as loci-specific DNA methylation of the promoter regions by pyrosequencing. All of these genes-MyoG, Hdac4, Trim63/ Murf1, Ampd3, Chrna1, and Fboxo32/Mafbx-have been identified previously via transcriptome-wide analysis of disuse-induced atrophy after neuromuscular blocker a-cobrotoxin treatment (42). In this investigation, we have identified novel data that suggest that MyoG, Trim63 (Murf1), Fbxo32 (Mafbx), and Chrna1 demonstrate reduced DNA methylation at specific time points after disuse-induced atrophy that corresponded with increases in gene expression at the same time points.…”

Section: Discussion Summarymentioning

confidence: 99%

Transcriptomic and epigenetic regulation of disuse atrophy and the return to activity in skeletal muscle

et al. 2017

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Physical inactivity and disuse are major contributors to age-related muscle loss. Denervation of skeletal muscle has been previously used as a model with which to investigate muscle atrophy following disuse. Although gene regulatory networks that control skeletal muscle atrophy after denervation have been established, the transcriptome in response to the recovery of muscle after disuse and the associated epigenetic mechanisms that may function to modulate gene expression during skeletal muscle atrophy or recovery have yet to be investigated. We report that silencing the tibialis anterior muscle in rats with tetrodotoxin (TTX)-administered to the common peroneal nerve-resulted in reductions in muscle mass of 7, 29, and 51% with corresponding reductions in muscle fiber cross-sectional area of 18, 42, and 69% after 3, 7, and 14 d of TTX, respectively. Of importance, 7 d of recovery, during which rodents resumed habitual physical activity, restored muscle mass from a reduction of 51% after 14 d TTX to a reduction of only 24% compared with sham control. Returning muscle mass to levels observed at 7 d TTX administration (29% reduction). Transcriptome-wide analysis demonstrated that 3714 genes were differentially expressed across all conditions at a significance of P £ 0.001 after disuse-induced atrophy. Of interest, after 7 d of recovery, the expression of genes that were most changed during TTX had returned to that of the sham control. The 20 most differentially expressed genes after microarray analysis were identified across all conditions and were cross-referenced with the most frequently occurring differentially expressed genes between conditions. This gene subset included myogenin (MyoG), Hdac4, Ampd3, Trim63 (MuRF1), and acetylcholine receptor subunit a1 (Chrna1). Transcript expression of these genes and Fboxo32 (MAFbx), because of its previously identified role in disuse atrophy together with Trim63 (MuRF1), were confirmed by real-time quantitative RT-PCR, and DNA methylation of their promoter regions was analyzed by PCR and pyrosequencing. MyoG, Trim63 (MuRF1), Fbxo32 (MAFbx), and Chrna1 demonstrated significantly decreased DNA methylation at key time points after disuseinduced atrophy that corresponded with significantly increased gene expression. Of importance, after TTX cessation and 7 d of recovery, there was a marked increase in the DNA methylation profiles of Trim63 (MuRF1) and Chrna1 back to control levels. This also corresponded with the return of gene expression in the recovery group back to baseline expression observed in sham-operated controls. To our knowledge, this is the first study to demonstrate that skeletal muscle atrophy in response to disuse is accompanied by dynamic epigenetic modifications that are associated with alterations in gene expression, and that these epigenetic modifications and gene expression profiles are reversible after skeletal muscle returns to normal

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Section: Discussion Summarymentioning

confidence: 99%

Transcriptomic and epigenetic regulation of disuse atrophy and the return to activity in skeletal muscle

et al. 2017

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“…Upregulated gene and/or protein expression of several components of the autophagy-lysosome system and/or accumulation of autophagic vacuoles has been observed in skeletal muscle of experimental models of acute and prolonged critical illness (55,322,434,490,616,690). Muscle disuse may be an important factor since multiple (though not all) studies on denervation-induced atrophy (model of chronic muscle disuse) also found such alterations, with one study additionally showing an increase in autophagic flux (356,525,526,715).…”

Section: Autophagy In Critical Illnessmentioning

confidence: 99%

“…Similarly, endotoxin administration activates caspase-3 and increases procaspase-3 levels in porcine muscle (530). Muscle caspase-3 mRNA levels were elevated in a rat ICU model of critical illness myopathy, but appeared relatively late and were preceded by both the upregulation of the E2 ligases (MuRF1 and atrogin-1) and the preferential myosin loss (434). However, total caspase activity was unaltered in muscles from critically ill patients (368).…”

Section: Caspase Involvement In Critical Illnessmentioning

confidence: 99%

“…Glycolytic capacity was preserved in caspase-1-deficient mice, identifying caspase-1 as a mediator of sepsis effects on muscle metabolism. LlanoDiez et al (434) found that caspase-1 mRNA was increased in a rat model of critical illness myopathy (rats mechanically silenced and ventilated for up to 14 days), a late-phase response observed after 9 -14 days. In the same window of time, mRNAs for caspase-4 and caspase-12 were also elevated, suggesting potential roles for these more obscure family members.…”

Section: Caspase Involvement 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

279

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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“…UPS is the major decomposition system in various myopathies causing muscle atrophy, such as inactivity, inflammation, cell energy stress, and malnutrition. The forkhead box O (FOXO) family of transcription factors stimulates the expression of two important regulators of UPS-mediated proteolysis of ubiquitin ligase atrogin-1 and muscle-specific RING finger protein-1 (MuRF1) [63][64][65]. In animal models, both MuRF1 and atrogin-1 recruitment, and UPS activation, mainly contribute to the loss of muscle mass, such as inactivation-induced atrophy, acute illness, chronic disease, and CIM [63,66,67].…”

Section: Early Phasementioning

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 wasting and the temporal gene expression pattern in a novel rat intensive care unit model

Cited by 64 publications

References 68 publications

Transcriptomic and epigenetic regulation of disuse atrophy and the return to activity in skeletal muscle

Transcriptomic and epigenetic regulation of disuse atrophy and the return to activity in skeletal muscle

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

Skeletal Muscle Dysfunction in Critical Illness

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