Novel Insights Into Mitochondria’s Role in Muscle Development and Dystrophy

Researchers at Peking University in China recently revealed new insights on the involvement of mitochondria in muscle development and muscular dystrophy in animal models. The study was recently published in the journal PLoS One and is entitled “Remodeling of Mitochondrial Flashes in Muscular Development and Dystrophy in Zebrafish”.

Mitochondria are small cellular organelles considered the powerhouse of cells where the energy for the body is produced. It is thought that mitochondria are highly diverse in a tissue- and cell type-specific manner, undergoing significant remodeling in different developmental stages or in the contexts of diseases and stress.

It has been recently shown that active mitochondria can undergo intermittent bursts of superoxide and reactive oxygen species (ROS) production, referred to as “mitochondrial flashes”. These reactive species, when present in high levels, can induce significant damage to cell structures and lead to the development of medical conditions. The mitochondrial flashes (or mitoflash) can be visualized through the use of biosensors (e.g., cpYFP) or chemical probes. The origin and regulation of mitoflash activity seems to be linked to core mitochondrial functions like energy metabolism, and to the mitochondrial response to stress stimuli like ROS.

In the study, researchers evaluated the developmental and disease-related remodeling of mitoflash activity in skeletal muscles of a zebrafish model of Duchenne muscular dystrophy (DMD), a human inherited disorder caused by a defective gene (dystrophin) that is characterized by a rapid progressive skeletal muscle weakness caused by chronic inflammation and the degeneration of muscle cells and tissue, which can compromise locomotion and the respiratory function, leading to breathing complications and cardio-respiratory failure. The team hypothesized that mitoflashes may be a biomarker of mitochondrial remodeling during skeletal muscle development. Transgenic zebrafish expressing the mitoflash reporter cpYFP were used in the study.

Researchers found prominent multiphasic changes in mitoflash frequency and properties according to the muscle type under development from 2 to 14 days post fertilization in the transgenic zebrafish. Furthermore, researchers observed short (S)-type mitoflashes mainly during early muscle formation, while during muscle maturation S-, transitory (T)- and regular (R)-type mitoflashes were detected according to their kinetics of decay, followed by a switch to R-type mitoflashes in mature skeletal muscles. This switch in mitoflash type was found to be in agreement with mitochondrial morphological changes. The team also found mitoflash changes in early development of muscular dystrophy in a zebrafish model of the disease, including remarkable cell-to-cell heterogeneity, increased mitoflash frequency, altered S- to R-type mitoflash transition and reduced levels of NAD(P)H (which is involved in the protective mechanism against ROS toxicity).

The research team concluded that during the development of skeletal muscles, as well as in diseased muscles, there is an intense functional and morphological remodeling of mitochondria accompanied by a profound developmental remodeling of mitoflash activity. The authors suggest that mitoflashes might represent a valuable physiological marker of mitochondrial function in animals under physiological but also pathophysiological conditions.