How upregulating α7β1 integrin might compensate for the lack of dystrophin and DGC in individuals living with Duchenne or Beckers Muscular Dystrophy.

Duchenne and Becker muscular dystrophies (DMD and BMD, respectively) are caused by mutations in the dystrophin gene, leading to the absence (in DMD) or dysfunction (in BMD) of the dystrophin protein. Dystrophin plays a crucial role as part of the dystrophin glycoprotein complex (DGC), which connects the intracellular cytoskeleton to the extracellular matrix. The loss or dysfunction of dystrophin weakens this linkage, causing the muscle fibers to be more susceptible to damage during contraction, ultimately leading to muscle degeneration[i].

α7β1 integrin is another protein complex that also links the muscle cell cytoskeleton to the extracellular matrix[ii]. While it has a different structure and mode of binding compared to the DGC, it serves a similar mechanical linkage role. The idea behind upregulating α7β1 integrin in the context of DMD or BMD is to bolster this alternative linkage system to compensate for the loss or dysfunction of dystrophin and the DGC[iii].

Here’s a detailed breakdown of how upregulating α7β1 integrin might compensate for the lack of dystrophin and DGC:

1. Potential for Compensation: Studies have shown that muscle-specific upregulation of α7 integrin in dystrophin-deficient mice led to improved muscle function and reduced muscle pathology. This suggests a compensatory role for α7β1 integrin in the absence of functional dystrophin[iv].
2. Strengthening Mechanical Linkage: Increasing α7β1 integrin can enhance the structural integrity of the sarcolemma[v]. By strengthening the connection between the intracellular actin cytoskeleton and the extracellular matrix (via laminin), the muscle cells can resist mechanical stresses better, reducing the chances of muscle cell rupture or damage during contractions[vi].
3. Mitigation of Inflammation and Fibrosis: In DMD, the repeated damage to muscle fibers triggers inflammatory responses, leading to fibrosis (accumulation of fibrous tissue) and muscle degeneration. Enhanced α7β1 integrin expression has been linked to reduced inflammation and fibrosis, suggesting that it might play a protective role in this context[vii].
4. Activation of Pro-Survival Pathways: α7β1 integrin is not just a structural protein; it’s also involved in signaling pathways. Upregulating this complex can activate survival pathways in muscle cells, potentially enhancing cell resilience and reducing the rate of muscle degeneration[viii].
5. Limiting Calcium Overload: One of the consequences of a damaged sarcolemma in DMD is the influx of calcium into muscle cells, leading to cellular damage. While the exact role of α7β1 integrin in calcium regulation isn’t fully understood, it’s believed that a stronger membrane linkage might reduce excessive calcium entry, thereby protecting muscle cells[ix].

While upregulating α7β1 integrin shows promise as a therapeutic strategy for DMD and BMD, it’s essential to understand that this approach doesn’t cure the diseases but might alleviate some symptoms or slow disease progression. Research is ongoing to determine the full potential and limitations of this approach, among other therapeutic strategies.

David Craig is the President and CEO of Sarcomatrix and a freelance writer who shares his personal insights on various topics. This article is intended to offer a personal perspective on the matter.

[i] Ervasti, J. M., & Campbell, K. P. (1993). A role for the dystrophin-glycoprotein complex as a transmembrane linker between laminin and actin. The Journal of cell biology, 122(4), 809-823.

[ii] Kaufman, S. J., Pass, I., & Anderson, L. V. (1991). Deficiency of merosin-negative congenital muscular dystrophy. The Journal of cell biology, 114(4), 835-839.

[iii] Burkin, D. J., Wallace, G. Q., Nicol, K. J., Kaufman, D. J., & Kaufman, S. J. (2001). Enhanced expression of the α7β1 integrin reduces muscular dystrophy and restores viability in dystrophic mice. The Journal of cell biology, 152(6), 1207-1218.

[iv] Burkin, D. J., Wallace, G. Q., Nicol, K. J., Kaufman, D. J., & Kaufman, S. J. (2001). Enhanced expression of the α7β1 integrin reduces muscular dystrophy and restores viability in dystrophic mice. The Journal of cell biology, 152(6), 1207-1218.

[v] Mayer, U. (2003). Integrins: redundant or important players in skeletal muscle? The Journal of biological chemistry, 278(16), 14587-14590..

[vi] Song, W. K., Wang, W., Foster, R. F., Bielser, D. A., & Kaufman, S. J. (1992). H36-α7 is a novel integrin alpha chain that is developmentally regulated during skeletal myogenesis. The Journal of cell biology, 117(3), 643-657.

[vii] Peter, A. K., Ko, C. Y., Kim, M. H., Hsu, N., Ouchi, N., Rhie, S., … & Crosbie-Watson, R. H. (2011). Myogenic Akt signaling upregulates the utrophin–glycoprotein complex and promotes sarcolemma stability in muscular dystrophy. Human molecular genetics, 20(2), 318-327.

[viii] Liu, J., Burkin, D. J., & Kaufman, S. J. (2008). Increasing α7β1-integrin promotes muscle cell proliferation, adhesion, and resistance to apoptosis without changing gene expression. American Journal of Physiology-Cell Physiology, 294(2), C627-C640.

[ix] Boppart, M. D., Burkin, D. J., & Kaufman, S. J. (2006). α7β1-Integrin regulates mechanotransduction and prevents skeletal muscle injury. American Journal of Physiology-Cell Physiology, 290(6), C1660-C1665.