Mitochondrial myopathy elicits global starvation response through FGF21

Progressive mitochondrial respiratory chain (RC) deficiency is associated with a wide spectrum of adult-onset degenerative diseases, as well as with normal aging. We have previously generated the Deletor mice to model late-onset progressive RC defects. Here we report novel tissue-specific pathways contributing to mitochondrial disease pathogenesis, identified by gene expression analysis. We found that RC-deficient muscle fibers secrete the fasting-induced hormone, fibroblast growth factor 21 (FGF21). This response leads to fatty acid recruitment from adipocytes and resistance to high-fat-diet induced obesity in mice, but does not affect glucose or insulin metabolism. FGF21 is also induced in the muscle of mitochondrial myopathy patients and in other RC-deficient mice. These data show that skeletal muscle is an endocrine organ, which signals its energy deficiency through FGF21. Furthermore, RC deficiency in single muscle fibers initiates a global starvation response. These data have important implications for conditions with primary or secondary RC deficiency.

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