The extracellular matrix (ECM) plays key roles in normal and diseased skeletal and cardiac muscle. In healthy muscle the ECM is essential for transmitting contractile force, maintaining myofiber integrity and orchestrating cellular signaling.
Duchenne Muscular Dystrophy (DMD) is caused by loss of
dystrophin, a cytosolic
protein that anchors a transmembrane complex and serves as a vital link between the actin cytoskeleton and the basal lamina. Loss of
dystrophin leads to membrane fragility and impaired signaling, resulting in myofiber death and cycles of
inflammation and regeneration.
Fibrosis is also a cardinal feature of DMD. In this review, we will focus on two cases where understanding the normal function and regulation of ECM in muscle has led to the discovery of candidate
therapeutics for DMD.
Biglycan is a small
leucine rich repeat ECM
protein present as two glycoforms in muscle that have dramatically different functions. One widely expressed form is
biglycan proteoglycan (PG) that bears two
chondroitin sulfate GAG chains (typically
chondroitin sulfate) and two N-linked
carbohydrates. The second glycoform, referred to as 'NG' (non-glycanated)
biglycan, lacks the GAG side chains. NG, but not PG
biglycan recruits
utrophin, an autosomal paralog of
dystrophin, and an NOS-containing signaling complex to the muscle cell membrane. Recombinant NG
biglycan can be systemically delivered to dystrophic mice where it upregulates
utrophin at the membrane and improves muscle health and function. An optimized version of NG
biglycan, 'TVN-102', is under development as a candidate therapeutic for DMD. A second matrix-embedded
protein being evaluated for therapeutic potential is latent TGFβ
binding protein 4 (LTBP4). Identified in a genomic screen for modifiers of
muscular dystrophy, LTBP4 binds both TGFβ and
myostatin. Genetic studies identified the hinge region of LTBP4 as linked to TGFβ release and contributing to the "hyper-TGFβ" signaling state that promotes
fibrosis in
muscular dystrophy. This hinge region can be stabilized by
antibodies directed towards this domain. Stabilizing the hinge region of LTBP4 is expected to reduce latent TGFβ release and thus reduce
fibrosis.