Elevated Protein Improves Muscle, Pulmonary Dysfunction in Duchenne Muscular Dystrophy Mouse Models

Researchers at the University of California investigated elevated levels of the protein sarcospan (SSPN) on skeletal muscle and pulmonary dysfunction in mice with Duchenne muscular dystrophy (DMD) and found notable improvements in disease symptoms.

The study, “High levels of sarcospan are well tolerated and act as a sarcolemmal stabilizer to address skeletal muscle and pulmonary dysfunction in DM,” was published in Human Molecular Genetics.

In patients with DMD, weakness and gradual loss of skeletal muscle is caused by genetic mutations that induce a progressive loss of complex muscle proteins that are important for stabilizing cellular muscle matrices during muscle contraction.

A previous study by the researchers demonstrated that human SSPN (hSSPN) could regulate the loss of those complex muscle proteins by fixing more adhesion complex proteins to the surface of the cell. In mice models, three times the amount of expressed hSSPN was found to enhance muscle membrane stability and prevent several underlying mechanisms that trigger DMD.

In the current study, the researchers investigated the tolerability and toxicity of elevated concentrations of the mouse SSPN (mSSPN) in mice with DMD.

Finding revealed that high levels of mSSPN are safe and without notable negative outcomes. They improved the cell membrane of the muscle fiber called sarcolemmal, and they resolved signs of muscular dystrophy such as enhanced resistance to muscle damage and decreased fatigue after exercise.

Other data suggested that higher levels of expressed mSSPN also affected pulmonary function in a good way, and decreased dystrophy signs in the diaphragm.

“Together, these results demonstrate that SSPN overexpression is well tolerated in mdx mice [models of DMD] and improves sarcolemma defects that underlie skeletal muscle and pulmonary dysfunction in DMD,” according to the study report.

Many DMD treatments currently under development aim to restore the sarcolemmal connection.

“SSPN is attractive as a potential therapeutic target, since it plays a direct role in stabilizing the sarcolemma, and additionally could serve to enhance localization of other adhesion complex proteins. This strategy is particularly appealing because it could also be used to augment other drug and gene therapies currently in development,’’ the authors wrote.