How do muscles repair damage? Newly discovered metabolic ‘switch’ provides an answer
Unveiling a cellular mechanism by which muscle stem cells repair damage, researchers spark hope for remedying muscle loss caused by injury, aging and weight-loss medications.
A team of scientists from the University of California, Irvine, the University of California, Los Angeles (both CA, USA) and Yale University (CT, USA) has furthered our understanding of how muscle damage is repaired by defining the metabolic shifts that underlie skeletal muscle differentiation. The findings could inspire novel treatments to help people recover lost muscle.
Precisely how muscle stem cells sense tissue damage and then orchestrate tissue repair remains something of a mystery in cell and tissue reprogramming. We know far more about what drives cellular identity in continually renewing tissues like the blood, intestine and skin than we do about quiescent stem cells of the muscle. Metabolism is involved in this cellular decision-making, but the basic mechanisms remain unclear.
As muscle stem cells are integral for tissue repair, understanding more about this process is integral if we are to therapeutically target stem cells to aid muscle recovery in human diseases like muscular dystrophy, cancer cachexia and diabetes.
In order to further explore the process of muscle repair, the researchers set out to identify a metabolic control mechanism for cell-level and tissue-level remodeling. To do this, they used a combination of metabolomics techniques to physically separate rate-limiting metabolic enzymes from their biochemical reactions in human muscle cell models and then deployed live-cell imaging to observe the impact.
In doing so, they revealed previously unknown spatiotemporal dynamics of PFK1, an enzyme that is essential for glycolysis, within the skeletal muscle lineage.
They discovered that the muscle isoform of PFK1, PFKM, is expressed at low levels in muscle stem cells, although this increases during differentiation.
When PFKM was temporally restricted, glucose metabolism shifted from glycolysis to the pentose phosphate pathway, which runs parallel to glycolysis and breaks down glucose to form NADPH and pentose sugars. PFKM overexpression increased glycolysis and promoted differentiation into terminally differentiated myofibers, while PFKM knockdown blunted differentiation.
Mechanistically, the researchers demonstrated that Wnt signalling rapidly induced lysosomal degradation of PFKM through a methyl arginine degron motif, which was selectively methylated and delivered to lysosomes through microautophagy.
At the same time, phenotypic and gene-based analyses suggested a role for PFKM in muscle health: reducing PFKM levels caused alterations in muscle differentiation and maturation in cultured cell models.
Essentially, muscle stem cells are able to reduce PFKM levels and temporarily pause metabolism, like a molecular switch, during early repair. Then, when PFKM returns, muscle building begins again.
Taken together, these findings highlight the importance of compartmentalized metabolism in cell fate decisions and could provide insight into strategies to reconstitute stem cell activity for tissue regeneration.
“We found that muscle stem cells actively change how they use nutrients to protect themselves first, then rebuild. That metabolic timing is critical,” the study’s corresponding author Lauren Albrecht noted.
“With the rapid rise of GLP-1 therapies and an aging population, preserving muscle mass has become a major health priority,” Albrecht continued. “Our work identifies a metabolic checkpoint that could one day be targeted to help people recover muscle more effectively.”