July 29, 2005Circulation Research
Transgenic Overexpression of Locally Acting Insulin-Like Growth Factor-1 Inhibits Ubiquitin-Mediated Muscle Atrophy in Chronic Left-Ventricular Dysfunction
Why the study?
Does transgenic overexpression of local insulin-like growth factor-1 prevent skeletal muscle atrophy in a mouse model of chronic left-ventricular dysfunction?
Population
Mice with experimental model of chronic left-ventricular dysfunction
Comparison
Transgenic overexpression of a local isoform of… vs Wild-type mice
Design
Preclinical
Follow-up
12 weeks
Authors
Discussion
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Member takes
Implication
Does not change clinical practice; leaves open IGF-1 pathway targeting for human HF cachexia.
Key Points
- To investigate the mechanisms of skeletal muscle proteolysis in chronic left-ventricular dysfunction and assess whether transgenic overexpression of local insulin-like growth factor-1 prevents muscle wasting.
- Induced chronic left-ventricular dysfunction via experimental myocardial infarction in wild-type and transgenic mice over a 12-week follow-up period.
- Engineered transgenic mice with muscle-specific overexpression of a locally acting isoform of insulin-like growth factor-1.
- Evaluated total protein ubiquitination, proteasome activity, myosin degradation, and activation of Foxo transcription factors and atrogin-1/MAFbx.
- Wild-type mice developed significant skeletal muscle atrophy 12 weeks post-infarction, driven by increased protein ubiquitination, elevated proteasome activity, Foxo activation, and robust induction of atrogin-1/MAFbx targeting muscle myosin.
- Transgenic overexpression of local insulin-like growth factor-1 prevented muscle atrophy and normalized proteasome activity.
- Local IGF-1 expression selectively inhibited the activation of Foxo4 and completely blocked the upregulation of the ubiquitin-protein ligase atrogin-1/MAFbx.
Structured PICO
Does transgenic overexpression of local insulin-like growth factor-1 prevent skeletal muscle atrophy in a mouse model of chronic left-ventricular dysfunction?
P
Population
Mice with experimental model of chronic left-ventricular dysfunction (12 weeks following myocardial infarction)
I
Intervention
Transgenic overexpression of a local isoform of insulin-like growth factor-1
C
Comparator
Wild-type mice
O
Outcome
Skeletal muscle atrophy and ubiquitin-proteasome pathway activity (protein ubiquitination, proteasome activity, Foxo activation, atrogin-1/MAFbx expression)surrogate
Local overexpression of IGF-1 prevents skeletal muscle atrophy in a mouse model of chronic heart failure by inhibiting the ubiquitin-proteasome pathway.
Cite This Study
Schulze et al. (2005) studied this question.