Constitutive activation of MAPK cascade in acute quadriplegic myopathy.
Acute quadriplegic myopathy (AQM; also called "critical illness myopathy") shows acute muscle wasting and weakness and is experienced by some patients with severe systemic illness, often associated with administration of corticosteroids and/or neuroblocking agents. Key aspects of AQM include muscle atrophy and myofilament loss. Although these features are shared with neurogenic atrophy, myogenic atrophy in AQM appears mechanistically distinct from neurogenic atrophy. Using muscle biopsies from AQM, neurogenic atrophy, and normal controls, we show that both myogenic and neurogenic atrophy share induction of myofiber-specific ubiquitin/proteosome pathways (eg, atrogin-1). However, AQM patient muscle showed a specific strong induction of transforming growth factor (TGF)-beta/MAPK pathways. Atrophic AQM myofibers showed coexpression of TGF-beta receptors, p38 MAPK, c-jun, and c-myc, including phosphorylated active forms, and these same fibers showed apoptotic features. Our data suggest a model of AQM pathogenesis in which stress stimuli (sepsis, corticosteroids, pH imbalance, osmotic imbalance) converge on the TGF-beta pathway in myofibers. The acute stimulation of the TGF-beta/MAPK pathway, coupled with the inactivity-induced atrogin-1/proteosome pathway, leads to the acute muscle loss seen in AQM patients.
Di Giovanni
Simone
S
Center for Genetic Medicine, Children's National Medical Center and Genetics Program, George Washington University, Washington, DC 20010, USA.
Molon
Annamaria
A
Broccolini
Aldobrando
A
Melcon
Gisela
G
Mirabella
Massimiliano
M
Hoffman
Eric P
EP
Servidei
Serenella
S
D000208:Acute Disease; D000368:Aged; D020869:Gene Expression Profiling; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008854:Microscopy, Electron; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009133:Muscular Atrophy / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009135:Muscular Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011782:Quadriplegia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
D016212:Transforming Growth Factor beta; D025801:Ubiquitin; D020928:Mitogen-Activated Protein Kinases