May 5, 2014

Mitochondrial Fusion May Explain Alcohol’s Effect on Muscle

Muscle fibers. A green fluorescent protein labels mitochondria in muscle fibers.Image by the researchers, courtesy of the Journal of Cell Biology

Scientists found that mitochondria in skeletal muscle form networks, fuse, and share components. Flaws in this process may contribute to muscle disorders. The results also suggest how prolonged alcohol consumption can lead to muscle weakness.

Skeletal muscles are made of long fibers packed with many highly organized proteins and organelles. Nestled among the protein machinery responsible for muscle contraction are mitochondria. These globular-shaped organelles provide energy for muscle and also help regulate the calcium signals that trigger muscle contraction.

Mitochondria undergo constant change. Defective parts are removed and replaced with new ones. Mitochondria can repair themselves through a process called mitochondrial fusion—joining with other mitochondria and exchanging material. The mitochondria in muscle, however, were presumed to be fairly isolated with little ability to interact with each other, due to the tissue’s compact organization.

A team led by Dr. György Hajnóczky at Thomas Jefferson University set out to visualize and measure fusion among muscle mitochondria to better understand their regulation and relevance in muscle disease. The work was funded in part by NIH’s National Institute on Alcohol Abuse and Alcoholism (NIAAA). Results appeared on April 28, 2014, in the Journal of Cell Biology.

The scientists labeled mitochondria in a small limb muscle in rats with fluorescent tags, including a green tag that was activated by light. About a week later, the muscle was removed, and single muscle fibers separated out and viewed under a microscope. Using pulses of light, the team observed the green label moving over time among mitochondria, suggesting that they were interconnected and could fuse with each other.

The group labeled mitochondria in several types of cultured muscle cells for comparison. Mitochondrial fusion was less frequent, but formed more stable connections, in rat muscle fibers than in less well-developed muscle cells. This may be because adult muscle fibers are more packed with highly organized proteins so that mitochondria are less mobile.

The team examined several mitochondrial proteins that are involved with fusion and may play a role in some muscle disorders. They found that fusion depended on the presence of mitofusin 1 (Mfn1), a protein located on the outer membrane of mitochondria.

Muscle weakness and fatigue are known to result from long-term alcoholism. To assess whether this might stem from an inability of mitochondria to fuse and thus repair themselves, the group fed rats ethanol for 6-11 months and then looked at labeled mitochondria. The fusion rate was reduced, and Mfn1 levels declined. When the team increased the amount of this protein in the muscles of ethanol-fed rats, they restored fusion activity.

In further experiments, the group found that disruptions in Mfn1 and fusion led to abnormal calcium regulation in mitochondria. Calcium signaling problems might thus account for defects in muscle function, such as fatigue.

“The finding gives insight into why chronic heavy drinking often saps muscle strength, and it could also lead to new targets for medication development,” says NIAAA Director Dr. George Koob. Other environmental factors might cause muscle fatigue by affecting mitochondria as well.

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References: Mitochondrial fusion is frequent in skeletal muscle and supports excitation-contraction coupling. Eisner V, Lenaers G, Hajnóczky G. J Cell Biol. 2014 Apr 28;205(2):179-95. doi: 10.1083/jcb.201312066. Epub 2014 Apr 21. [Epub ahead of print] PMID: 24751540.

Funding: NIH’s National Institute on Alcohol Abuse and Alcoholism (NIAAA); Pew Latin American Fellows Program in the Biomedical Sciences; and the Duchenne Parent Project, Netherlands.