Delivering the gene for METTL14, a protein that works with a partner to add chemical marks to RNA, to heart cells reduced scarring in mice with progeria, a disease of accelerated aging, and extended lifespan in one of two mouse lines
Delivering the gene for METTL14, a protein that works with a partner to add chemical marks to RNA, to heart cells reduced scarring in mice with progeria, a disease of accelerated aging, and extended lifespan in one of two mouse lines
On 15 October, a group from Shenzhen University published a study in Aging Cell. METTL14 levels were lower in the hearts of mice with progeria and old mice than in healthy and young mice, respectively. Delivering its gene with a viral vector reduced fibrosis, the accumulation of scar tissue, and the activity of the gene encoding interferon-beta, an inflammatory signal, in two mouse lines with progeria. Lifespan also increased in one of the lines.
Children with progeria most often die of a heart attack or heart failure. The disease is caused by progerin, a defective form of lamin A, a protein of the nuclear envelope. Blood vessels in progeria lose elasticity, placing strain on the heart, while the contribution of the heart muscle cells themselves, called cardiomyocytes, to heart failure has remained disputed. To investigate their contribution, the authors used tamoxifen to induce progerin production specifically in the cardiomyocytes of two-month-old mice. By five months of age, their hearts contained more collagen, the main protein in scar tissue, than those of mice without progerin. Their hearts pumped an average of 10,4 ml of blood per minute rather than 14,1, and their lifespan was shorter.
The choice of METTL14 was based on a mechanism proposed by the same group in 2020: lamin A “tethers METTL14 to nuclear speckles through direct interaction”, protecting the protein from degradation. Nuclear speckles are clusters of RNA-processing proteins within the nucleus. This tethering is disrupted in progeria, and patients’ cells contain less METTL14. Adding METTL14 to old human skin cells reduced the proportion of cells with a senescence marker from 72% to less than 20%.
METTL14 and METTL3 work together to add the m6A mark to RNA, chemically modifying adenine. This mark influences how long some RNAs persist and, consequently, protein production. Levels of both proteins were lower in the hearts of three mouse lines with progeria (one with progerin confined to the heart and two with disease affecting the whole body) than in controls. Levels were also lower in 18-month-old mice than in three-month-old mice; no difference was found in the kidneys of old mice.
To determine how a shortage of METTL14 affects RNA, the researchers suppressed the protein in cultured cardiomyocytes from newborn mice. Interferon-beta RNA became more abundant and persisted longer: its half-life, the time it takes for half the molecules to degrade, increased from 1,7 to 3,3 hours. By contrast, the half-life of RNA encoding calsequestrin-2, a protein that stores calcium for heart muscle cell contraction, fell from 10,8 to 5,9 hours. Both RNAs also carried fewer marks in the hearts of mice with progerin throughout the body. Suppressing calsequestrin-2 itself increased the activity of a collagen gene and two cellular senescence genes in cardiomyocytes.
The researchers then gave mice with progerin confined to cardiomyocytes a viral vector carrying the METTL14 gene, with expression restricted to heart cells. Control mice received the same vector without the gene. Two months later, METTL3 levels in the heart had also increased. Calsequestrin-2 RNA levels had returned to normal, interferon and collagen gene RNA levels had fallen, and stained heart sections showed less collagen.
To test whether restoring METTL14 in the heart alone could help when the disease affects the whole body, the researchers gave the same vector to mice lacking the Zmpste24 gene. In these mice, lamin A fails to mature, and average lifespan is about 20 weeks rather than more than two years. Their hearts contained almost six times as much calsequestrin-2 RNA as those of control mice, while RNA levels for interferon-beta and collagen genes were lower. Mice given METTL14 also stayed on a rotating rod longer. Median lifespan was higher in 7 treated mice than in 16 control mice.