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RNA-sequencing reveals altered skeletal muscle contraction, E3 ligases, autophagy, apoptosis, and chaperone expression in patients with critical illness myopathy.

ABSTRACT: BACKGROUND:Critical illness myopathy (CIM) is associated with severe skeletal muscle wasting and impaired function in intensive care unit (ICU) patients. The mechanisms underlying CIM remain incompletely understood. To elucidate the biological activities occurring at the transcriptional level in the skeletal muscle of ICU patients with CIM, the gene expression profiles, potential upstream regulators, and enrichment pathways were characterized using RNA sequencing (RNA-seq). We also compared the skeletal muscle gene signatures in ICU patients with CIM and genes perturbed by mechanical loading in one leg of the ICU patients, with an aim of reducing the loss of muscle function. METHODS:RNA-seq was used to assess gene expression changes in tibialis anterior skeletal muscle samples from seven critically ill, immobilized, and mechanically ventilated ICU patients with CIM and matched control subjects. We also examined skeletal muscle gene expression for both legs of six ICU patients with CIM, where one leg was mechanically loaded for 10?h/day for an average of 9?days. RESULTS:In total, 6257 of 17,221 detected genes were differentially expressed (84% upregulated; p?

SUBMITTER: Llano-Diez M

PROVIDER: S-EPMC6466682 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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RNA-sequencing reveals altered skeletal muscle contraction, E3 ligases, autophagy, apoptosis, and chaperone expression in patients with critical illness myopathy.

Llano-Diez Monica M Fury Wen W Okamoto Haruka H Bai Yu Y Gromada Jesper J Larsson Lars L

Skeletal muscle 20190416 1

<h4>Background</h4>Critical illness myopathy (CIM) is associated with severe skeletal muscle wasting and impaired function in intensive care unit (ICU) patients. The mechanisms underlying CIM remain incompletely understood. To elucidate the biological activities occurring at the transcriptional level in the skeletal muscle of ICU patients with CIM, the gene expression profiles, potential upstream regulators, and enrichment pathways were characterized using RNA sequencing (RNA-seq). We also compa ...[more]

PMID: 30992050

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Project description:Ubiquitination is a dynamic post-translational modification that regulates the fate of proteins and therefore modulates a myriad of cellular functions. At the last step of this sophisticated enzymatic cascade, E3 ubiquitin ligases selectively direct ubiquitin attachment to specific substrates. Altogether, the ?800 distinct E3 ligases, combined to the exquisite variety of ubiquitin chains and types that can be formed at multiple sites on thousands of different substrates confer to ubiquitination versatility and infinite possibilities to control biological functions. E3 ubiquitin ligases have been shown to regulate behaviors of proteins, from their activation, trafficking, subcellular distribution, interaction with other proteins, to their final degradation. Largely known for tagging proteins for their degradation by the proteasome, E3 ligases also direct ubiquitinated proteins and more largely cellular content (organelles, ribosomes, etc.) to destruction by autophagy. This multi-step machinery involves the creation of double membrane autophagosomes in which engulfed material is degraded after fusion with lysosomes. Cooperating in sustaining homeostasis, actors of ubiquitination, proteasome and autophagy pathways are impaired or mutated in wide range of human diseases. From initial discovery of pathogenic mutations in the E3 ligase encoding for E6-AP in Angelman syndrome and Parkin in juvenile forms of Parkinson disease, the number of E3 ligases identified as causal gene for neurological diseases has considerably increased within the last years. In this review, we provide an overview of these diseases, by classifying the E3 ubiquitin ligase types and categorizing the neurological signs. We focus on the Gigaxonin-E3 ligase, mutated in giant axonal neuropathy and present a comprehensive analysis of the spectrum of mutations and the recent biological models that permitted to uncover novel mechanisms of action. Then, we discuss the common functions shared by Gigaxonin and the other E3 ligases in cytoskeleton architecture, cell signaling and autophagy. In particular, we emphasize their pivotal roles in controlling multiple steps of the autophagy pathway. In light of the various targets and extending functions sustained by a single E3 ligase, we finally discuss the challenge in understanding the complex pathological cascade underlying disease and in designing therapeutic approaches that can apprehend this complexity.

Dataset Information

RNA-sequencing reveals altered skeletal muscle contraction, E3 ligases, autophagy, apoptosis, and chaperone expression in patients with critical illness myopathy.

Publications

RNA-sequencing reveals altered skeletal muscle contraction, E3 ligases, autophagy, apoptosis, and chaperone expression in patients with critical illness myopathy.

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