DOCK3 regulates normal skeletal muscle regeneration and glucose metabolism

bioRxiv, 2023 · DOI: https://doi.org/10.1101/2023.02.22.529576 · Published: February 27, 2023

Simple Explanation

This research explores the role of the DOCK3 protein in skeletal muscle function, regeneration, and glucose metabolism. Prior studies have shown DOCK3 upregulation in muscular dystrophy. To study DOCK3's function exclusively in muscle, the researchers created mice with DOCK3 selectively knocked out in skeletal muscle. The knockout mice exhibited hyperglycemia, increased fat mass, impaired muscle architecture, reduced locomotor activity, and impaired myofiber regeneration. These results indicate DOCK3 plays a crucial role in maintaining skeletal muscle health, independently of its function in neuronal lineages. The study identified a novel interaction between DOCK3 and SORBS1, an insulin adaptor protein, potentially explaining the metabolic dysregulation observed. This suggests that DOCK3 is essential for skeletal muscle regeneration and metabolic regulation.

Study Duration

Not specified

Participants

Dock3 conditional skeletal muscle knockout mice (Dock3 mKO) and control mice

Evidence Level

Not specified

Key Findings

1
Dock3 mKO mice presented with significant hyperglycemia and increased fat mass, indicating a metabolic role in the maintenance of skeletal muscle health.
2
Dock3 mKO mice had impaired muscle architecture, reduced locomotor activity, impaired myofiber regeneration, and metabolic dysfunction.
3
A novel DOCK3 interaction with SORBS1 through the C-terminal domain of DOCK3 that may account for its metabolic dysregulation was identified.

Research Summary

This study investigates the role of DOCK3 in skeletal muscle using a muscle-specific knockout mouse model. The researchers found that loss of DOCK3 in skeletal muscle leads to impaired muscle regeneration, metabolic dysfunction, and reduced locomotor activity. The study identifies a novel protein-protein interaction between DOCK3 and SORBS1, an insulin signaling protein, suggesting a mechanism for DOCK3's role in glucose metabolism in skeletal muscle. The findings demonstrate that DOCK3 is essential for normal skeletal muscle function, regeneration, and metabolic regulation, independent of its function in neuronal lineages.

Practical Implications

Therapeutic Target for Muscular Dystrophy

DOCK3 could be a potential therapeutic target for treating muscle wasting diseases, such as Duchenne muscular dystrophy, by modulating its expression or activity in skeletal muscle.

Understanding Metabolic Disorders

The novel DOCK3-SORBS1 interaction provides insights into the molecular mechanisms regulating insulin signaling and glucose uptake in skeletal muscle, which could contribute to developing new treatments for metabolic disorders like type 2 diabetes.

Improving Muscle Regeneration

Understanding the role of DOCK3 in muscle regeneration may lead to strategies to enhance muscle repair after injury or in age-related muscle loss (sarcopenia).

Study Limitations

1
The study primarily uses mouse models, and further research is needed to confirm the findings in human subjects.
2
The precise molecular mechanisms by which DOCK3 regulates muscle regeneration and glucose metabolism require further investigation.
3
The study focuses on the role of DOCK3 in skeletal muscle, but its potential interactions with other tissues and systems were not extensively explored.

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