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I?B? degradation is necessary for skeletal muscle atrophy associated with contractile claudication.

ABSTRACT: The arterial blockage in patients with peripheral arterial disease (PAD) restricts oxygen delivery to skeletal muscles distal to the blockage. In advanced-stage PAD patients, this creates a chronic ischemic condition in the affected muscles. However, in the majority of PAD patients, the muscles distal to the blockage only become ischemic during physical activity when the oxygen demands of these muscles are increased. Therefore, the skeletal muscle of most PAD patients undergoes repeated cycles of low-grade ischemia-reperfusion each time the patient is active and then rests. This has been speculated to contribute to the biochemical and morphological myopathies observed in PAD patients. The current study aimed to determine, using a rodent model, whether repeated hind limb muscle contractions during blood flow restriction to the hind limb muscles increases NF-?B activity. We, subsequently, determined whether an increase in NF-?B activity during this condition is required for the increased transcription of specific atrophy-related genes and muscle fiber atrophy. We found that hind limb muscle contractions during blood flow restriction to the limb increased NF-?B activity, the transcription of specific atrophy-related genes, and caused a 35% decrease in muscle fiber cross-sectional area. We further found that inhibition of NF-?B activity, via gene transfer of a dominant-negative inhibitor of ?B? (d.n. I?B?), prevented the increase in atrophy gene expression and muscle fiber atrophy. These findings demonstrate that when blood flow to skeletal muscle is restricted, repeated cycles of muscle contraction can cause muscle fiber atrophy that requires NF-?B-I?B? signaling.

SUBMITTER: Hain BA

PROVIDER: S-EPMC6195647 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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IκBα degradation is necessary for skeletal muscle atrophy associated with contractile claudication.

Hain Brian A BA Dodd Stephen L SL Judge Andrew R AR

American journal of physiology. Regulatory, integrative and comparative physiology 20110105 3

The arterial blockage in patients with peripheral arterial disease (PAD) restricts oxygen delivery to skeletal muscles distal to the blockage. In advanced-stage PAD patients, this creates a chronic ischemic condition in the affected muscles. However, in the majority of PAD patients, the muscles distal to the blockage only become ischemic during physical activity when the oxygen demands of these muscles are increased. Therefore, the skeletal muscle of most PAD patients undergoes repeated cycles o ...[more]

PMID: 21209383

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Project description:Skeletal muscle atrophy is a consequence of many diseases, environmental insults, inactivity, age and injury. Atrophy is characterized by active degradation and removal of contractile proteins and a reduction in fiber size. Animal models have been extensively used to identify pathways leading to atrophic conditions. Here we have used genome-wide expression profiling analysis and quantitative PCR to identify the molecular changes that occur in two clinically relevant animal mouse models of muscle atrophy, hindlimb casting and Achilles tendon laceration (tenotomy). Gastrocnemius muscle samples were collected 2, 7 and 14 days after insult. The total amount of muscle loss as measured by wet weight and muscle fiber size was equivalent between models, although tenotomy resulted in a more rapid induction of muscle atrophy. Furthermore, tentomy resulted in the regulation of significantly more mRNA transcripts then casting. Analysis of the regulated genes and pathways suggest that the mechanism of atrophy is distinct between these models. The degradation following casting appears ubiquitin-proteasome-mediated while degradation following tenotomy appears lysosomal and matrix-metalloproteinase (MMP)-mediated. This data suggests that there are multiple mechanisms leading to muscle atrophy and that specific therapeutic agents may be necessary to combat the atrophy seen under different conditions. Muscle atrophy was induced through two methods; unloading induced by tendon laceration (Tenotomy) and immobilization induced by hindlimb casting (Casting). For the tenotomy, eight week old male C57/B6 mice were anesthetized by ether inhalation and subsequent intramuscular injection of ketamine-xylazine (0.1 ml/g). The right Achilles tendon just proximal to the calcaneus was severed with a sterile scalpel. The mice were allowed to recover and move freely about their cage. An additional cohort of animals was sham operated (Sham) which involved isolation and manipulation of the Achilles tendon without laceration. For the casting, the right hindlimbs of eight week old male C57Bl/6 mice were immobilized through casting. After 2, 7 or 14 days, animals were sacrificed and the left and right gastrocnemius muscles were carefully removed, flash frozen in liquid nitrogen, and stored at -80°C for further processing. The left untreated legs served as controls. A group of naïve animals that received no treatment or manipulation was included as an additional control. Each group consisted of between 5 and 10 samples for a total of 111 individual samples.

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I?B? degradation is necessary for skeletal muscle atrophy associated with contractile claudication.

Publications

IκBα degradation is necessary for skeletal muscle atrophy associated with contractile claudication.

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