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The mechanisms by which mitochondrial function and contractile fiber type are concordantly regulated to ensure muscle function remain poorly understood. Evidence is emerging that the Folliculin interacting protein 1 (<jats:italic>Fnip1<\/jats:italic>) is involved in skeletal muscle fiber type specification, function, and disease. In this study,<jats:italic>Fnip1<\/jats:italic>was specifically expressed in skeletal muscle in<jats:italic>Fnip1<\/jats:italic>-transgenic (<jats:italic>Fnip1<\/jats:italic><jats:sup>Tg<\/jats:sup>) mice.<jats:italic>Fnip1<\/jats:italic><jats:sup>Tg<\/jats:sup>mice were crossed with<jats:italic>Fnip1-<\/jats:italic>knockout (<jats:italic>Fnip1<\/jats:italic><jats:sup>KO<\/jats:sup>) mice to generate<jats:italic>Fnip1<\/jats:italic><jats:sup>TgKO<\/jats:sup>mice expressing<jats:italic>Fnip1<\/jats:italic>only in skeletal muscle but not in other tissues. Our results indicate that, in addition to the known role in type I fiber program, FNIP1 exerts control upon muscle mitochondrial oxidative program through AMPK signaling. Indeed, basal levels of FNIP1 are sufficient to inhibit AMPK but not mTORC1 activity in skeletal muscle cells. Gain-of-function and loss-of-function strategies in mice, together with assessment of primary muscle cells, demonstrated that skeletal muscle mitochondrial program is suppressed via the inhibitory actions of FNIP1 on AMPK. Surprisingly, the FNIP1 actions on type I fiber program is independent of AMPK and its downstream PGC-1\u03b1. These studies provide a vital framework for understanding the intrinsic role of FNIP1 as a crucial factor in the concerted regulation of mitochondrial function and muscle fiber type that determine muscle fitness.<\/jats:p>","DOI":"10.1371\/journal.pgen.1009488","type":"journal-article","created":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T17:37:53Z","timestamp":1617039473000},"page":"e1009488","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":42,"title":["AMPK-dependent and -independent coordination of mitochondrial function and muscle fiber type by 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