BMAL1, SIRT2, and the Timing of Myelin Repair
In mice, metformin produced more new myelin-forming cells when administered at a specific time of day
On 7 August, Neuron published a study of the cells that rebuild the myelin sheath around nerve fibers after injury. In a mouse model, metformin produced more new oligodendrocytes when administered at ZT12, when the lights were switched off and the mice entered their active phase. The authors linked this effect to the protein SIRT2.
Myelin surrounds nerve fibers and allows signals to travel rapidly. After injury, oligodendrocytes rebuild this sheath. Oligodendrocytes develop from precursor cells called OPCs. These cells first leave their resting state and divide, then mature and begin producing myelin. This transition becomes impaired with age, resulting in poorer myelin repair after injury.
The authors studied BMAL1, a gene involved in regulating the cell's circadian rhythm. In old mice, the daily fluctuations in this gene's activity became less pronounced in OPCs. The cells remained at rest more often, entered division and maturation less often, and showed impaired energy metabolism. When the researchers switched off Bmal1 specifically in the OPCs of young mice, the cells developed signs of senescence, a state in which a cell stops dividing after stress, and were less able to mature into myelin-forming oligodendrocytes.
The team then induced focal myelin damage in the corpus callosum of young adult mice whose OPCs lacked Bmal1 and in control animals. For eight days, the researchers administered metformin at two different times of day. Treatment at ZT12 produced more new oligodendrocytes in the damaged tissue than treatment at ZT0, when the lights were switched on. Metformin and β-NMN showed the same time-dependent effect in synchronized cultures of OPCs lacking Bmal1. β-NMN is a precursor of NAD+, a molecule that SIRT2 requires to function. When the researchers suppressed Sirt2, metformin and β-NMN no longer restored the cells' ability to divide and mature.
In control OPCs, SIRT2 levels peak at ZT12, when cellular energy metabolism is most active. The treatment time used in the experiment coincided with this phase. The authors also found abnormalities in BMAL1 and SIRT2 in precursor cells grown from cells obtained from patients with multiple sclerosis and in tissue from disease lesions.
In 2019, another group showed in aging rats that metformin restored the ability of old OPCs to mature and improved remyelination. The new study shows that, in a model of myelin injury, the outcome of the same treatment can depend on the time of day. Precursor cells follow their own circadian schedule when maturing into oligodendrocytes.