Loss of muscle mass is a universal issue in aging, leading a degree that leads to physical frailty. Beyond this, muscle is also metabolically active, such as via the production of myokines, and loss of muscle mass is harmful to the rest of the body via these and other signaling mechanisms that remain to be fully explored. Researchers here note the transcription factor MYC as a target for the development of enhancement therapies producing muscle growth. Overexpression of the Yamanaka factor MYC is something to be careful with, given its role in cancer and reprogramming. The classes of therapy presently explored by the reprogramming community, intended to produce repeated short-term expression of Yamanaka factors, seem needed here. Many of the same challenges and caveats will likely apply, such as those regarding targeting to specific cell types and the different cell populations in a tissue requiring different timing and levels of expression for optimal effect.
Several seminal and recent studies suggest that the transcription factor c-Myc (referred to as Myc or MYC for mouse and human genes, respectively) is a key component of skeletal muscle hypertrophic adaptation to loading in animals. Our work using human skeletal muscle biopsies after a bout of resistance exercise (RE), as well as meta-analytical information that combines numerous human muscle gene expression datasets during the recovery period after exercise, indicates that MYC is highly responsive to hypertrophic loading. MYC protein accumulates in human muscle following a bout of RE as well as in response to chronic training. Its expression may also differentiate between low and high hypertrophic responders.
The current investigation details the global gene expression response to a bout of RE after 30 minutes, 3-, 8-, and 24-hours using RNA-sequencing (RNA-seq) in skeletal muscle biopsy samples from healthy untrained humans. Molecular and computational analyses identified MYC as an influential transcription factor controlling the exercise transcriptome throughout the time course of recovery after a bout of RE. Muscle-specific Myc overexpression data from the plantaris and soleus of mice reinforced the human exercise data.
We employed a genetically modified mouse model to induce MYC in a pulsatile fashion specifically in skeletal muscle over 4 weeks to determine if MYC is sufficient for hypertrophy. Our genetically driven pulsatile approach avoids potential negative effects of chronically overexpressing a hypertrophic regulator and more closely mimics the transient molecular response of exercise in skeletal muscle. Pulsed MYC induction resulted in a larger absolute mass (+12.5%) and normalized mass (+20.7%) of the soleus muscle relative to controls. This magnitude of soleus muscle growth is similar to what is observed after 4 weeks of progressive weighted wheel running.
Link: https://doi.org/10.1038/s44319-024-00299-z
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