Nature sub-journal: Sphingolipids accumulate in aging muscle, and blocking their synthesis can restore muscle health

With age, muscle mass and strength will be gradually lost, and skeletal muscle dysfunction and quality decline are one of the most important reasons for the decline in function and loss of independence in the
elderly.
Age-related muscle dysfunction and sarcopenia are the leading causes of physical disability in older adults, but viable treatment strategies
are currently lacking.

On December 16, 2022, researchers from the Ecole Polytechnique Fédérale de Lausanne in Switzerland published a research paper
in Nature Aging: Sphingolipids accumulate in aged muscle, and their reduction counteracts sarcopenia.

The study found that sphingolipids accumulate in mouse skeletal muscle with aging, and inhibition of sphingolipid synthesis could prevent age-related loss of muscle mass while enhancing strength and exercise capacity
.
In the sphingolipid metabolic pathway, the accumulation of dihydroceramide is the culprit that interferes with myofibril homeostasis
.

The study also further verified the correlation of sphingolipid synthesis in human aging, in which reduced expression of SPTLC1 gene and DEGS1 gene was associated with
improved and reduced health in the elderly, respectively.

These findings identify inhibition of sphingolipid synthesis as an attractive therapeutic strategy
for the treatment of age-related sarcopenia.

Ceramide, a core component of sphingolipid metabolism, found that when mice aged, their muscles were heavily filled with ceramides, and the team wanted to see if reducing ceramides could prevent age-related decline in muscle function
.
They treated elderly mice with ceramide blockers (e.
g.
, myriocin, Takeda-2) or used adeno-associated virus (AAV) vectors to block ceramide synthesis
in muscle.
The results showed that blocking ceramides prevented the loss of muscle mass during aging, making the mice stronger, allowing them to run farther, and improving their motor coordination
.

To investigate this effect more deeply, the research team measured all known gene transcripts in the muscles using RNA sequencing technology, and the results showed that blocking ceramide production was able to activate muscle stem cells, allowing muscles to produce more protein and shift the fiber type to rapid contraction glycolysis, resulting in larger and stronger muscles
in older mice.

Finally, the research team investigated whether reducing ceramides in muscles could also be beneficial
in humans.
They found that people with reduced sphingolipid synthesis in their muscles because of genetic mutations (reduced levels of SPTLC1 gene expression) had stronger muscles and better healthy aging
.

Overall, the study found that ceramides accumulate in skeletal muscle during aging, and that blocking ceramide synthesis from pharmacological or genetic levels was able to counteract age-related losses
in muscle mass and function in aging mice.
The study also further demonstrates the correlation between ceramide synthesis and aging in humans, where mutations with reduced SPTLC1 gene expression levels are associated with improved muscle mass in older adults, while mutations with reduced DEGS1 gene expression levels are associated
with decreased muscle mass in older adults.

These findings suggest that inhibition of sphingolipid synthesis is a novel strategy for the treatment of senile sarcopenia, and given the multiple cellular functions and involvement of ceramides in multiple diseases, treating multiple diseases with only one biological pathway is an attractive therapeutic strategy
to combat multiple age-related diseases.

Johan Auwerx, corresponding author of the paper, said that these findings are important and provide a strong impetus
for us to develop inhibitors of sphingolipid synthesis that can be tested in humans.
It is reported that the research team is working with the pharmaceutical industry to develop it
.