When we’re young, our muscles are pretty good at recovering from injuries. The reason for this is that young muscle can regenerate damaged muscle cells, called myofibers, in such a way that their original structure is restored. This is important because a precise cellular architecture in muscle tissue enables proper muscle function.
However, as we age, we gradually lose this advantage. Following an injury, old muscle just doesn’t regenerate like it used to. The ability to restore muscle cell architecture is eventually lost and, over time, we get weaker.
Now, a study led by researchers at the University of Pittsburgh reveals that age-related loss of a “longevity protein”, called α-Klotho (‘alpha’-Klotho), may be to blame.
The name Klotho, by the way, is a nod to one of the three Fates in Greek mythology who spun the thread of human life. The protein α-Klotho had been previously linked with anti-ageing and longevity, but its role in young and ageing muscle was unclear.
Fabrisia Ambrosio at the University of Pittsburgh and her colleagues discovered that, in young muscle, higher levels of α-Klotho are produced following muscle injury. It seems young muscle is able to ramp up α-Klotho production by making critical ‘epigenetic’ changes in the aftermath of an injury.
A genetic on/off switch
Our DNA contains multitudes of genes, but in order for our cells to function properly, or indeed perform different functions altogether, the activity of those genes must be tightly controlled.
Patterns of small molecules, called methyl groups, decorate the surface our DNA and serve as ‘epigenetic’ signals that essentially tell the cell which genes to turn on and off at any given time. Moreover, the patterns of these methyl groups can change in response to a wide variety of environmental cues, including injury.
The researchers found that when young muscle is injured, the muscle cells are able to make temporary changes to methyl group patterns that control the α-Klotho gene, switching production into high gear.
They also discovered that ageing muscles lose this ability to turn on α-Klotho activity after injury. When old muscle is injured, there’s no increase in α-Klotho levels.
The researchers went on to show that if α-Klotho production is inhibited in young mice, those mice exhibit a similar decline in muscle function to ageing mice.
Conversely, when older mice were administered α-Klotho following injury, their muscle regeneration improved.
"We found that we were able to rescue, at least in part, the regenerative defect of aged skeletal muscle," said Ambrosio.
"We saw functional levels of muscle regeneration in old animals that paralleled those of their young counterparts, suggesting that this could potentially be a therapeutic option down the road."
Helping the cell’s powerhouse
It’s thought that α-Klotho is beneficial to the function of muscle cell mitochondria (the energy powerhouse of a cell). Ambrosio and her colleagues discovered that α-Klotho is very important for the maintenance of mitochondrial structure, and the ability to repair DNA damage in the mitochondria. By extension, it’s very important for the energetics of a muscle cell. Furthermore, they confirmed that loss of α-Klotho leads to mitochondrial dysfunction.
Ambrosio and her colleagues wanted to know if a drug called SS-31 would help offset the problems caused by loss of α-Klotho because SS-31, which is currently in clinical trials, is known to target the mitochondria.
Sure enough, when mice with α-Klotho deficiency were given SS-31 after injury, their muscle regeneration improved and strength recovery also improved. This was only observed for mice with insufficient α-Klotho; SS-31 did not improve muscle regeneration in healthy mice with normal α-Klotho levels.
Improving α-Klotho production or mitochondrial function in ageing muscle could one day assist muscle regeneration in older humans. However, Ambrosio cautions that due to the complex nature of α-Klotho’s role in mitochondrial function and damage repair, the timing, dosage and route of administration of any such intervention will need to be carefully examined.
"If you just bombard the muscle with Klotho, we do not expect to observe any functional benefit," Ambrosio said. "We've found that mimicking the timing profile we see in young animals seems to be critical. We think that this gives some insight into the therapeutic window."
The findings have been published in the journal Nature Communications.
I am a science writer with a Bachelor of Science in physics and a PhD in biophysics. I have researched distant stars, extremophiles and the fine-tuned architecture of proteins. Along the way I clocked many midnights at telescopes, lab benches, and the occasional particle acc...MORE