Muscle membrane integrity in Duchenne muscular dystrophy: recent advances in copolymer-based muscle membrane stabilizers

Abstract

The scientific premise, design, and structure-function analysis of chemical-based muscle membrane stabilizing block copolymers are reviewed here for applications in striated muscle membrane injury. Synthetic block copolymers have a rich history and wide array of applications from industry to biology. Potential for discovery is enabled by a large chemical space for block copolymers, including modifications in block copolymer mass, composition, and molecular architecture. Collectively, this presents an impressive chemical landscape to leverage distinct structure-function outcomes. Of particular relevance to biology and medicine, stabilization of damaged phospholipid membranes using amphiphilic block copolymers, classified as poloxamers or pluronics, has been the subject of increasing scientific inquiry. This review focuses on implementing block copolymers to protect fragile muscle membranes against mechanical stress. The review highlights interventions in Duchenne muscular dystrophy, a fatal disease of progressive muscle deterioration owing to marked instability of the striated muscle membrane. Biophysical and chemical engineering advances are presented that delineate and expand upon current understanding of copolymer-lipid membrane interactions and the mechanism of stabilization. The studies presented here serve to underscore the utility of copolymer discovery leading toward the therapeutic application of block copolymers in Duchenne muscular dystrophy and potentially other biomedical applications in which membrane integrity is compromised.

Dysregulation of Calcium Handling in Duchenne Muscular Dystrophy-Associated Dilated Cardiomyopathy: Mechanisms and Experimental Therapeutic Strategies

“…Finally, P188-treated mdx mice undergoing chronic isoproterenol stress had some improvements in in vivo cardiac function after two and four weeks [158], and a large animal model of DMD showed significant improvement in in vivo cardiac function after chronic P188 therapy [68]. The reader is referred to excellent recent reviews for more details on this topic [63,166].…”

“…First, dystrophin, as part of the DGC, connects the extracellular matrix and the intracellular cytoskeleton and acts as a "shock absorber" for the sarcolemma during the repeated stress of contraction and relaxation [62][63][64]. Sarcolemmal stress in the absence of dystrophin leads to muscle membrane damage or micro-tears, causing extracellular calcium influx and calcium overload [20,62,63] (Figure 3). Secondly, dystrophin acts as a scaffolding protein to localize and normalize function of proteins involved in intracellular calcium and redox homeostasis.…”

“…Membrane stabilization has been extensively studied as a therapeutic strategy for DMD cardiomyopathy in both small and large animal models [41,68] to mitigate sarcolemmal damage and calcium overload occurring from mechanical stress in the absence of dystrophin. Triblock copolymers, of which Poloxamer 188 (P188) has been most widely studied, consist of a hydrophobic polypropylene oxide (PPO) core, flanked by two hydrophilic polyethylene oxide (PEO) chains [63]. P188 is thought to insert into damaged membranes to provide stability until intrinsic repair mechanisms are able to restore integrity of the membrane [63].…”

“…Triblock copolymers, of which Poloxamer 188 (P188) has been most widely studied, consist of a hydrophobic polypropylene oxide (PPO) core, flanked by two hydrophilic polyethylene oxide (PEO) chains [63]. P188 is thought to insert into damaged membranes to provide stability until intrinsic repair mechanisms are able to restore integrity of the membrane [63]. P188 treatment of isolated dystrophic cardiac myocytes improved membrane compliance and decreased calcium influx and hypercontracture during passive physiological stretch [41].…”

Multi-Compartment, Early Disruption of cGMP and cAMP Signalling in Cardiac Myocytes from the mdx Model of Duchenne Muscular Dystrophy

“…This complex localizes at the plasmalemma and links the actin cytoskeleton to the extracellular matrix, playing an important structural role. Lack of this complex disrupts sarcolemmal integrity and causes mechanical instability that results in easily damaged muscle fibers [ 5 ]. Components of the DAPC are also involved in non-structural functions, including modulation of intracellular calcium and redox homeostasis and the absence of dystrophin causes disrupted localisation and abnormal expression/activity of these proteins, leading to calcium mishandling and oxidative stress [ 6 ].…”