AAV‐Mediated nuclear localized PGC1α4 delivery in muscle ameliorates sarcopenia and aging‐associated metabolic dysfunctions

Abstract

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 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‐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.

Glucocorticoid intermittence coordinates rescue of energy and mass in aging-related sarcopenia through the myocyte-autonomous PGC1alpha-Lipin1 transactivation

“…Regarding both aspects, our data here pave the way to several compelling questions for the aging muscle, including shared/differential mechanisms of PGC1alpha isoforms and which co-factors are engaged by the GR in beneficial versus deleterious muscle contexts. It is interesting to emphasize that our findings are consistent with not only genetic experiments with PGC1alpha isoforms 8–10,40 but also with scattered reports regarding the metabolic link between PGC1alpha activation and growth. For instance, PGC1alpha was found to integrate oxidative and growth pathways downstream of caloric restriction 11 , a generally positive intervention in the context of aging and muscle health.…”

“…PGC1alpha impact on metabolism is balanced at the level of its splice variants 7 . Besides the canonical longer PGC1alpha-isoform 1 that regulates mitochondrial biogenesis and function, the shorter PGC1alpha-isoform 4 has been identified in mice and humans from an alternative transcription start site 8 and is sufficient to increase muscle mass and strength in cachectic muscle 9 and sarcopenia 10 . A previous study with caloric restriction reported correlations between PGC1alpha upregulation in aging muscle and activation of growth pathways in addition to mitochondrial function 11 .…”

Myospreader improves gene editing in skeletal muscle by myonuclear propagation

“…Both base and prime editors are large (>197kDa) fusions consisting of a Cas9 fused to DNA targeted enzymatic domains (41)(42)(43)(44), and additional fusions are being employed for epigenetic editing, transcriptional activation, and transcriptional repression (8,9,(45)(46)(47). Many other myonuclear-targeted cargoes are also under development, such as a DUX4 dominant negative for Facioscapulohumeral dystrophy (48), Pumilio-PIN fusions for myotonic dystrophy (49), and PGC1a for sarcopenia (50). All of these approaches can in principle benefit from the enhanced myonuclear propagation and protein stability provided by Myospreader or other NLS/NES combinations.…”