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Updated: Mar 16, 2026

Measurement of Insulin- and Contraction-Stimulated Glucose Uptake in Isolated and Incubated Mature Skeletal Muscle from Mice
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Measurement of Insulin- and Contraction-Stimulated Glucose Uptake in Isolated and Incubated Mature Skeletal Muscle from Mice

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Insulin and IGF-1 receptors regulate FoxO-mediated signaling in muscle proteostasis

Brian T O'Neill, Kevin Y Lee, Katherine Klaus

    The Journal of Clinical Investigation
    |August 16, 2016
    PubMed

    Insights

    Insulin receptor (IR) signaling is crucial for skeletal muscle mass and protein balance, more so than IGF-1 receptor (IGF1R) signaling. Combined deletion of IR and IGF1R in mice leads to muscle loss, which is reversed by inhibiting autophagy via FoxO factors.

    Area of Science:

    • Muscle physiology
    • Metabolic signaling
    • Cellular proteostasis

    Background:

    • Diabetes significantly disrupts skeletal muscle protein metabolism.
    • Insulin (via IR) and IGF-1 (via IGF1R) signaling pathways are key regulators of muscle protein synthesis.
    • The distinct and overlapping roles of IR and IGF1R in maintaining muscle proteostasis remain incompletely understood.

    Purpose of the Study:

    • To investigate the relative and combined contributions of insulin receptor (IR) and IGF-1 receptor (IGF1R) signaling to skeletal muscle proteostasis.
    • To elucidate the downstream mechanisms, including protein degradation pathways and transcription factors, involved in IR/IGF1R-mediated muscle regulation.

    Main Methods:

    • Generation and analysis of mice with muscle-specific knockout of IR (M-IR-/-), IGF1R (M-IGF1R-/-), or both (MIGIRKO).
    • Assessment of muscle mass, protein synthesis and degradation rates (proteasomal and autophagy-lysosomal pathways).
    • Investigation of the role of FoxO transcription factors (FoxO1, FoxO3, FoxO4) in regulating muscle proteostasis in MIGIRKO mice.

    Main Results:

    • IR signaling plays a predominant role in maintaining differentiated skeletal muscle mass compared to IGF1R signaling.
    • Combined deletion of IR and IGF1R in MIGIRKO mice resulted in significant muscle mass reduction, increased protein degradation via both proteasomal and autophagy-lysosomal systems, indicating a high protein turnover state.
    • Muscle-specific deletion of FoxO1, FoxO3, and FoxO4 in MIGIRKO mice rescued muscle mass by reversing autophagy-mediated degradation, without affecting proteasomal activity.

    Conclusions:

    • Insulin receptor signaling is more critical than IGF-1 receptor signaling for maintaining proteostasis in differentiated skeletal muscle.
    • Coordinated IR and IGF1R signaling is essential for regulating muscle protein turnover.
    • Suppression of FoxO-driven autophagy is a key mechanism through which IR/IGF1R signaling maintains skeletal muscle mass.

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