Mitochondrial Protein’s Loss Linked to Muscle Weakness and Poor Repair in Early Study

Mitochondrial Protein’s Loss Linked to Muscle Weakness and Poor Repair in Early Study

Loss of MICU1, a key regulator of calcium balance in cells, was seen to affect muscle function and repair in a study in mice and cells from people lacking this mitochondrial protein.

These findings support the involvement of MICU1 in neuromuscular disorders, its researchers said, and its potential as a treatment target in diseases like muscular dystrophy.

The study, “Dysregulation of Mitochondrial Ca2+ Uptake and Sarcolemma Repair Underlie Muscle Weakness and Wasting in Patients and Mice Lacking MICU1,” was published in the journal Cell Reports.

A proper balance of calcium inside muscle fibers is critical for muscle contraction and relaxation, energy metabolism, and muscle repair. The uptake of calcium by mitochondria — the energy producers or powerhouses of cells — via MICU1 is important for each of these functions.

“Control of calcium transport by MICU1 helps to coordinate muscle fibers and their mitochondria,” György Hajnóczky, MD, PhD, the study’s lead author and director of the MitoCare Center at Thomas Jefferson University, said in a press release.

“Disruption of this link,” he added, “prevents the proper communication between mitochondria and the rest of the muscle, making the muscle easier to damage and unable to exert as much force.”

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Calcium imbalance in mitochondria has been suggested as a key player in multiple neuromuscular and neurodegenerative conditions, including muscular dystrophy. Up to 60 patients with muscle fatigue and weakness have also been found to lack the MICU1 protein, the study reports.

But the underlying mechanisms between this imbalance and disease are not fully understood.

Researchers studied a mouse model they created to specifically lack MICU1 in skeletal muscles, and samples of muscle fibroblasts (cells that produce collagen to support muscle) from patients without any MICU1 protein.

In both cases, loss of the protein meant lower than usual levels of calcium in mitochondria. This suggests that a cell’s mitochondrial can no longer sense the appropriate level of calcium to take up, creating an imbalance in muscle fibers.

A calcium imbalance in muscle fibers lacking MICU1 prevented muscles from working normally. When stimulated, muscle fibers showed poorer contraction. Affected mice also showed greater fatigue with exercise and muscle atrophy (shrinkage), similar to symptoms seen in the patients lacking MICU1, the scientists said.

Studies of mouse models of limb girdle muscular dystrophy 2B have shown that skeletal muscle degeneration is often caused by an inability to repair the muscle membrane. And in mice with Duchenne muscular dystrophy, dysregulation of calcium and mitochondrial proteins were seen to occur early in the disease, and also associated with poor muscle membrane repair.

For these reasons, the researchers also studied the effects of MICU1 loss on muscle repair.

Muscle damage was induced by having mice lacking MICU1 run on a downhill treadmill. They then used a dye that could  cross the muscle membrane to assess muscle repair. Greater repair would correlate with lesser evident dye.

Lower muscle membrane repair was seen in the mice, and also in fibroblasts — damaged by a laser — taken from people lacking MICU1.

Restoring protein levels in fibroblasts led to repair in muscle fibers, again indicating that MICU1 loss promoted muscle damage.

“This means that mitochondrial calcium uptake is important for normal repair of muscle, and this was not known before,” said Erin Seifert, PhD, a study author.

“So, boosting this control mechanism could potentially aid in muscle recovery after exercise, especially if the control mechanism is compromised,” she added.

Overall, these findings support the use of MICU1 as a potential target for treating neuromuscular diseases such as muscular dystrophy,

“[T]his work links the loss of control of mitochondrial Ca2+ [calcium ions] to impaired adaptation of oxidative metabolism and exhaustion, and reveals poor plasma membrane repair as a pathogenic mechanism for the clinical symptoms, which may be targetable for therapy,” the study concluded.

Patricia holds a Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She has also served as a PhD student research assistant at the Department of Microbiology & Immunology, Columbia University, New York.
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José is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer’s disease.
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Patricia holds a Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She has also served as a PhD student research assistant at the Department of Microbiology & Immunology, Columbia University, New York.
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