PGC-1α4 Gene Therapy Reduces Sarcopenia and Metabolic Disease in Aged Mice

Researchers here demonstrate that aged muscle metabolism can be improved via gene therapy to deliver a short isoform of PGC-1α. Upregulating PGC-1α in muscle tissue is suggested to be a good approach to therapy based on its declining expression with age. It is interesting that the researchers focus on an isoform of the protein shown to be upregulated in exercise, in effect aiming to produce an exercise mimetic gene therapy that switches on one of the reactions to exercise and leaves it switched on indefinitely.

Sarcopenia is characterized of muscle mass loss and functional decline in elder individuals which severely affects human physical activity, metabolic homeostasis, and life quality. Physical exercise is considered effective in combating muscle atrophy and sarcopenia, yet it is not feasible to elders with limited mobility. PGC-1α4, a short isoform of PGC-1α, is strongly induced in muscle under resistance training, and promotes muscle hypertrophy. In the present study, we showed that the transcriptional levels and nuclear localization of PGC1α4 was reduced during aging, accompanied with muscle dystrophic morphology, and gene programs. We thus designed NLS-PGC1α4, a nuclear localization sequence attached to PGC1α4, and ectopically express it in myotubes to enhance PGC1α4 levels and maintain its location in nucleus.

Indeed, NLS-PGC1α4 overexpression increased muscle sizes in myotubes. In addition, by utilizing AAV-mediated NLS-PGC1α4 delivery into gastrocnemius muscle, we found that it could improve sarcopenia with grip strength, muscle weights, fiber size, and molecular phenotypes, and alleviate age-associated adiposity, insulin resistance, and hepatic steatosis, accompanied with altered gene signatures. Mechanistically, we demonstrated that NLS-PGC-1α4 improved insulin signaling and enhanced glucose uptake in skeletal muscle. Besides, via RNA-seq analysis, we identified myokines IGF1 and METRNL as potential targets of NLS-PGC-1α4 that possibly mediate the improvement of muscle and adipose tissue functionality and systemic energy metabolism in aged mice. Moreover, we found a negative correlation between PGC1α4 and age in human skeletal muscle.

Together, our results revealed that NLS-PGC1α4 overexpression improves muscle physiology and systematic energy homeostasis during aging and suggested it as a potent therapeutic strategy against sarcopenia and aging-associated metabolic diseases.


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