PGC-1a isoform heterodimerization restricts transcription factor docking and limits metabolic adaptations in skeletal muscle

The PGC-1a gene is expressed as several transcriptional coactivator variants that regulate numerous adaptive processes. These include thermogenesis, hepatic metabolism, neuroprotection, and skeletal muscle adaptation to exercise training. To support such diverse functions, PGC-1? isoform expression and activation are under tight tissue- and context-specific control. Notably, PGC-1? isoforms generated by alternative gene promoter usage, and splicing are highly induced in skeletal muscle upon exercise. Here we show that PGC-1?2 and ?3 are PGC-1?1 dimerization partners that limit its activity. Skeletal muscle PGC-1?2 and PGC-1?3 transgenics have reduced exercise performance and strength, which partially overlaps with PGC-1? loss-of-function. Mechanistically, PGC-1?1/?3 dimerization precludes ERR? recruitment and coactivation, so their co-expression in skeletal muscle impairs the innate bioenergetic adaptations characteristic of PGC-1?1 transgenics and reduces oxidative metabolism gene expression and exercise capacity. Removing this break to PGC-1a1 activity may have therapeutic applications in metabolic diseases and increase responsiveness to training. Overall design: Gastrocnemius muscle from either wild-type or HSA-PGC-1a3 transgenic mouse was used for RNASeq analysis to determine the overall changes of transcriptome of PGC-1a3 mice.