TY - JOUR
T1 - Constitutive activation of MAPK cascade in Acute Quadriplegic Myopathy
AU - Di Giovanni, Simone
AU - Molon, Annamaria
AU - Broccolini, Aldobrando
AU - Melcon, Gisela
AU - Mirabella, Massimiliano
AU - Hoffman, Eric P
AU - Servidei, Serenella
PY - 2004
Y1 - 2004
N2 - 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.
AB - 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.
KW - AQM
KW - MAPK
KW - apoptosis
KW - muscle atrophy
KW - AQM
KW - MAPK
KW - apoptosis
KW - muscle atrophy
UR - https://publicatt.unicatt.it/handle/10807/115852
UR - https://www.scopus.com/inward/citedby.uri?partnerID=HzOxMe3b&scp=0842304360&origin=inward
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=0842304360&origin=inward
U2 - 10.1002/ana.10811
DO - 10.1002/ana.10811
M3 - Article
SN - 0364-5134
SP - 195
EP - 206
JO - Annals of Neurology
JF - Annals of Neurology
IS - 55
ER -