Toll-Like Receptors as a Therapeutic Target for Muscular Dystrophy 2020


Senior Member
Progressive Skeletal Muscle Atrophy in Muscular Dystrophies: A Role for Toll-Like Receptor-Signaling in Disease Pathogenesis
Boel De Paepe

Neuromuscular Reference Center, Ghent University Hospital, Corneel Heymanslaan 10, 9000 Ghent, Belgium
Int. J. Mol. Sci. 2020, 21(12), 4440;


Muscle atrophy is an active process controlled by specific transcriptional programs, in which muscle mass is lost by increased protein degradation and/or decreased protein synthesis.

This review explores the involvement of Toll-like receptors (TLRs) in the muscle atrophy as it is observed in muscular dystrophies, disorders characterized by successive bouts of muscle fiber degeneration and regeneration in an attempt to repair contraction-induced damage.

TLRs are defense receptors that detect infection and recognize self-molecules released from damaged cells.

In muscular dystrophies, these receptors become over-active, and are firmly involved in the sustained chronic inflammation exhibited by the muscle tissue, via their induction of pro-inflammatory cytokine expression.

Taming the exaggerated activation of TLR2/4 and TLR7/8/9, and their downstream effectors in particular, comes forward as a therapeutic strategy with potential to slow down disease progression.

Muscular dystrophies are hereditary disorders caused by defects in a plethora of genes involved in muscle protein expression and organization....

The most common type is Duchenne muscular dystrophy (DMD), a severe X-linked disorder that affects 1 in 3500 boys born worldwide. .....
The disease usually presents in early childhood as progressive muscle weakness, which causes loss of ambulation by early adolescence.....

A milder form of muscular dystrophy associated with DMD defects is Becker muscular dystrophy, a condition in which mutations in the gene lead to production of truncated, yet partially functional dystrophin protein.

The limb girdle muscular dystrophies (LGMDs), a heterogeneous group of diseases caused by different gene defects, represent the second most common dystrophy, and associate with predominant shoulder girdle and pelvic muscle weakness.....

Facioscapulohumeral muscular dystrophy (FSHD) most often affects facial, shoulder blade, and upper arm muscles, with patients displaying prolonged muscle contractions. FSHD can be distinguished into 2 types, with FSHD1 being by far the most common form, accounting for 95 percent of cases. ....

Myotonic dystrophy is the most common adult onset muscular dystrophy and is inherited in an autosomal dominant pattern.

The inflammatory component of muscular dystrophy pathogenesis is of pivotal importance for tissue regeneration via delicately regulated elimination and replacement. Damaged muscle fibers are cleared by inflammatory cells to allow new fibers to take their place.

The complex interplay of soluble factors and adhesion molecules tightly regulates these immune responses. Myofibers become active participants in the regulation and recruitment of inflammatory cells, by inducing the major histocompatibility complex I (MHC-I) on their sarcolemma and by producing regulatory cytokines, steering the inflammation forward.

These capabilities of dystrophic muscle cells to act as immune-active regulators have also been confirmed through in vitro studies. Myoblasts from LGMD patients with LMNA defects, constitutively secrete high levels of IL-6 and IL-8 [5], an expression pattern which resembles closely that of damaged cells.

Other muscle tissue constituents, including blood vessels and infiltrating inflammatory cells, participate in the immune cascades, of which soluble cytokines are key regulators. DMD patients’ sera display elevated levels of interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α [6], and certain chemokines including CC-motif chemokine ligand (CCL) 2, CCL14, CXC-motif chemokine ligand (CXCL) 12, and CXCL14 [7].

Macrophages and other cytotoxic immune cells clear the muscle tissue of necrotic fibers, and most abundantly express CXCL8, CCL2, and CCL5. CCL2 in particular is produced by and targets monocytes and T-cells, driving forward inflammation in a self-amplifying process [8].

Initially started to allow muscle tissue recovery, inflammation perpetuates past its desired time point, aggravating damage.

The important role played by the immune system means that immunosuppression is, at this time, standard treatment for DMD.

Glucocorticoids mitigate symptoms and add years to patient mobility, but come with important side effects and do not represent a true cure for the disease.