Temporal phosphoproteomics reveals circuitry of phased propagation in insulin signaling.
Summary
Time-resolved phosphoproteomics in human primary myotubes mapped ~13,000 phosphosites and uncovered phased activation/deactivation of distinct subcellular pathways during insulin signaling. Network integration revealed novel non-canonical nodes and linked insulin-induced spliceosome phosphorylation to acute alternative splicing.
Key Findings
- Tracked ~13,000 phosphopeptides over time in insulin-stimulated human myotubes.
- Revealed time-phased, non-overlapping pathway activation and deactivation during insulin signaling.
- Identified novel non-canonical signaling candidates and key regulatory nodes via PPI-informed network analysis.
- Linked insulin-regulated phosphorylation of the pre-catalytic spliceosome to acute alternative splicing in human skeletal muscle.
Clinical Implications
Identifies candidate regulatory nodes and time windows that could be leveraged to fine-tune insulin responses therapeutically; highlights spliceosome modulation as a potential axis in insulin resistance.
Why It Matters
Provides a high-resolution temporal atlas of insulin signaling in human muscle and connects signaling dynamics to RNA processing, expanding targets for metabolic disease research.
Limitations
- In vitro myotube model lacks systemic in vivo complexity and hormonal milieu.
- Functional validation of many nominated nodes in organisms is pending.
Future Directions
Validate key nodes and spliceosome links in vivo; map temporal signaling alterations in insulin resistance and type 2 diabetes muscle.
Study Information
- Study Type
- Case-control
- Research Domain
- Pathophysiology
- Evidence Level
- V - Mechanistic omics study in primary human cells; no clinical outcomes.
- Study Design
- OTHER