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NF‐kappa B signaling and skeletal muscle fiber atrophy: a rodent model of exercise with restricted blood supply, and Peripheral Arterial Disease patients
Author(s) -
Judge Andrew R,
Hain Brian A,
Dodd Stephen L,
Pipinos Iraklis
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1092.25
Subject(s) - skeletal muscle , muscle atrophy , atrophy , medicine , endocrinology , myocyte , tumor necrosis factor alpha , tibialis anterior muscle
Skeletal muscles distal to the arterial blockage in Peripheral Arterial Disease (PAD) patients become ischemic during physical activity due to a mismatch between blood supply and the oxygen demands of the muscle. Thus, skeletal muscles of PAD patients undergo repeated cycles of ischemia‐reperfusion daily as the patient is active, then rests. We hypothesize that this contributes to the muscle atrophy observed in PAD patients. The current work used a rodent model to determine whether repeated bouts of muscle contraction with restricted blood supply increases nuclear factor kappa B (NF‐κB) signaling and causes skeletal muscle fiber atrophy. The femoral artery of rats was ligated (Lig) to restrict blood supply to muscles distal to the ligation and in vivo electrical stimulation (Stim) was used to cause repeated muscle contractions. Muscles were stimulated for 15 min, 4x/day, for 5 days. Lig & Stim caused an 18‐fold increase in NF‐κB activity, increased the expression of specific atrophy‐related genes and caused a 35% decrease in skeletal muscle fiber cross sectional area, which were all abolished by in vivo gene transfer of a dominant negative inhibitor of κB α (IκBα). An NF‐κB signaling pathway PCR array identified that several transcripts of the tumor necrosis factor alpha (TNF‐α) and interleukin‐1 (IL‐1) pathways were up‐regulated in Lig & Stim muscles AND in the skeletal muscle of PAD patients. Treatment of C2C12 skeletal muscle cells with TNF‐α, IL‐1β or TNF‐α plus IL‐1β confirmed that these cytokines, alone and in combination, increase NF‐κB‐dependent transcription and atrophy gene expression. In conclusion, repeated muscle contractions (exercise) with restricted blood supply causes skeletal muscle atrophy which requires NF‐κB activation. Supported by a James & Esther King Biomedical Research Program Grant, 08KN‐07.