Exploring the complex relationship between insulin-like growth factors and myofascial pain syndrome
Myofascial pain syndrome is characterized by the presence of myofascial trigger points—hyperirritable spots within taut bands of muscle fibers that can cause both localized and referred pain 4 . These aren't ordinary muscle knots; they're complex zones of dysfunction where muscle fibers contract excessively, blood flow becomes compromised, and a cocktail of inflammatory substances accumulate, creating a vicious cycle of pain and discomfort 9 .
Cause spontaneous pain, tenderness, and restricted range of motion even without pressure.
Only cause pain when pressed but can still restrict movement and alter muscle function.
Affecting up to 85% of people at some point in their lives, myofascial pain syndrome remains one of the most common causes of musculoskeletal pain worldwide.
To understand the emerging connection between IGFs and muscle pain, we first need to explore what these fascinating molecules are. Insulin-like growth factors, primarily IGF-1 and IGF-2, are proteins strikingly similar in structure to insulin, but with vastly different functions 6 . Think of them as the body's master regulators of growth and repair—they're essential for muscle development, nerve cell survival, and tissue regeneration throughout our lives 1 .
Primarily regulated by growth hormone, plays crucial roles in childhood growth and continues to have anabolic effects in adults.
Mannally expressed gene, important for fetal development but also plays roles in adults, particularly in the nervous system.
"Increased levels of insulin-like growth factors may be required for the repair mechanisms after exercise" 1 .
Here's where the story gets intriguing: research has revealed a complex, almost paradoxical relationship between IGFs and pain. On one hand, IGFs possess anti-inflammatory and protective properties that should theoretically reduce pain. They've been shown to protect against ischemic injury in both nervous system tissue and skeletal muscle, and they play roles in maintaining normal nociceptive function (how we perceive painful stimuli) 1 .
To unravel this paradox, scientists have turned to animal models that allow them to examine the precise molecular mechanisms at play. A groundbreaking 2025 study published in Scientific Reports took this approach, using a rat model of myofascial trigger points to investigate how IGF-1 receptor (IGF-1R) activation influences pain 5 .
Established a reliable animal model of myofascial trigger points by inducing repeated blunt trauma to the gastrocnemius (calf) muscle of rats, combined with eccentric exercise.
Assessed pain-like behaviors using the Randall-Selitto test, which measures mechanical withdrawal threshold.
Using techniques like Western blot and immunohistochemistry, researchers measured levels of IGF-1, IGF-1R, and key proteins in the suspected pain signaling pathway.
Some animals received either an IGF-1R inhibitor (picropodophyllin) or a PI3K inhibitor (LY294002) to block specific steps in the suspected pain pathway.
| Research Reagent | Primary Function | Significance in MPS Research |
|---|---|---|
| Picropodophyllin (PPP) | IGF-1R inhibitor | Blocks IGF-1 receptor activation; reversed hyperalgesia in MPS models |
| LY294002 | PI3K inhibitor | Blocks downstream signaling pathway; demonstrated analgesic effects |
| Anti-IGF-1 neutralizing antibodies | Binds and neutralizes IGF-1 | Reduces mechanical allodynia and thermal hyperalgesia in pain models |
| Recombinant IGF-1 | IGF-1R agonist | Activates IGF-1 receptor; used to test direct effects on pain sensitivity |
| Hematoxylin and Eosin (HE) stain | Tissue morphology visualization | Revealed structural changes in muscle fibers with MTrPs |
| Experimental Group | Effect on Mechanical Withdrawal Threshold | Time of Peak Effect |
|---|---|---|
| MTrPs Model (untreated) | Significant decrease | Progressive over 2 weeks |
| MTrPs + IGF-1R inhibitor | Significant increase | 1 hour post-injection |
| MTrPs + PI3K inhibitor | Significant increase | 2 hours post-injection |
| Control + IGF-1 agonist | Significant decrease | 2 hours post-injection |
So how exactly does IGF-1 receptor activation translate into the experience of pain? The research points to an intricate molecular cascade that amplifies pain signals:
When IGF molecules bind to their receptors on muscle and nerve cells, it triggers phosphorylation events, changing protein shape and function 6 .
The activated receptor then triggers the PI3K/AKT pathway, acting like an internal relay race passing signals within the cell 5 .
This cascade influences proteins like mTOR and RhoA, heightening nociceptive sensitivity—turning up the volume on pain signals 5 .
| Protein | Function | Role in MPS Pain |
|---|---|---|
| IGF-1R | Cell surface receptor for IGFs | Significantly elevated in MTrPs; initiates pain signaling |
| PI3K | Intracellular signaling enzyme | Relays pain signal from IGF-1R; inhibition reverses hyperalgesia |
| AKT | Serine/threonine-specific protein kinase | Key intermediate signaling molecule; phosphorylated in active pathway |
| mTOR | Serine/threonine kinase regulating cell growth | Downstream target associated with hyperalgesia; promotes peripheral sensitization |
| RhoA | Small GTPase protein | Regulates actin cytoskeleton; implicated in contractile features of MTrPs |
The investigation into insulin-like growth factors and myofascial pain syndrome represents a fascinating convergence of growth biology and pain research. What emerges is not a simple story of "good molecules gone bad," but rather a complex narrative about biological balance and context. IGFs, crucial for muscle health and repair, appear to have a dark side when their signaling becomes dysregulated—particularly through the IGF-1R and its downstream PI3K/AKT/mTOR pathway 5 .
The journey from recognizing a painful muscle knot to understanding the IGF signaling pathways that may sustain it represents precisely the kind of scientific detective work that could transform how we treat one of humanity's most common ailments. While questions remain—such as why IGF-2 levels decrease in MPS patients and what determines individual variations in IGF signaling—each discovery brings us closer to reconciling the healer and harmdoer aspects of these fascinating growth factors.