Interplay between SLIRP activity and exercise training sheds light on mitochondrial plasticity in skeletal muscle

Mitochondrial dysfunction has been linked to a reduction in muscle mass and strength observed in patients with conditions such as cancer, type 2 diabetes, and sarcopenia. Recently, a research group at the University of Copenhagen, led by Dr Tang Cam Phung Pham and Associate Professor Lykke Sylow, identified the protein SLIRP as a key regulator of mitochondrial function at rest.

Following the knockout of SLIRP in mouse skeletal muscles, they demonstrated that mitochondrial structure and respiration were severely compromised. Further, they proposed a mechanism for SLIRP-independent mitochondrial function, highlighting the plasticity of the organelle and providing insight into approaches that can mitigate mitochondrial dysfunction.

Utilizing recombinant AAV produced by VectorBuilder, the group was able to overexpress SLIRP and highlight the importance of other proteins involved, including LRPPRC, a co-stabilizer of SLIRP. Overexpression of SLIRP alone was not sufficient to enhance total SLIRP protein levels, emphasizing the importance of LRPPRC in SLIRP-mediated regulation of mitochondrial function. Comparable to observations in mouse models, the team demonstrated that both proteins were upregulated in response to exercise training in humans, indicating a similar mechanism of mitochondrial regulation was at play. Interestingly, they found that exercise training could reverse the detrimental effects caused by loss of SLIRP in mouse models, likely by enhancing the capacity of the mitochondria to produce proteins.

“VectorBuilder has greatly assisted our research, facilitating hypothesis testing through intramuscular injections of recombinant adeno-associated viral serotype 6 (rAAV6):Slirp vectors. The support from their team ensured that the vector met our needs, and their production methods delivered reliable results. We appreciate their valuable contribution to our research,” Dr. Tang Cam Phung Pham said.

Overall, this study provides insights into the regulation of mitochondrial function in skeletal muscle, which could inform future treatment strategies for pathologies linked to mitochondrial dysfunction.

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Source: Pham, P.C.T., Raun, H.S., Havula, E. et al. The mitochondrial mRNA stabilizing protein, SLIRP, regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanisms. bioRxiv (2023). doi: https://doi.org/10.1101/2023.10.30.564600