Chung et al. show that the myomitokine GDF15 can act to modulate oxidative and lipolytic function in a non–cell-autonomous manner, thereby regulating systemic energy homeostasis in skeletal muscle-specific Crif1-deficient mice. This pathway may be a potential therapeutic target for preventing the onset of obesity and insulin resistance.

Summary Management of energy stores is critical during endurance exercise, with a shift in substrate utilization from glucose towards fat being a hallmark of trained muscle. Here we show that this key metabolic adaptation is both dependent on muscle PPARδ and stimulated by PPARδ ligand. Furthermore, we find that muscle PPARδ expression positively correlates with endurance performance in BXD mouse reference populations. In addition to stimulating fatty acid metabolism in sedentary mice, PPARδ activation potently suppresses glucose catabolism and does so without affecting either muscle fiber type or mitochondrial content. By preserving systemic glucose levels PPARδ acts to delay the onset of hypoglycemia and extends running time by ~100 minutes in treated mice. Collectively, these results identify a bifurcated PPARδ program that underlies glucose sparing and highlight the potential of PPARδ-targeted exercise mimetics in the treatment of metabolic disease, dystrophies and unavoidably, the enhancement of athletic performance.

Burmese pythons display a dramatic increase in heart mass after a large meal. We investigated the molecular mechanisms of this physiological heart growth, with the goal of applying this knowledge to the mammalian heart. We found that heart growth in pythons is characterized by myocyte hypertrophy in the absence of cell proliferation and by activation of PI3K/Akt/mTor signaling pathways. Despite high levels of circulating lipids, the postprandial python heart does not accumulate triglycerides or fatty acids. Instead, there is robust activation of pathways of fatty acid transport and oxidation combined with increased expression and activity of the cardioprotective enzyme, superoxide dismutase. Finally, we identified a combination of fatty acids in python plasma that promotes physiological heart growth when injected into either pythons or mice.

Highlights d USP30 and March5 reciprocally modify import substrates at the TOM complex d USP30 promotes mitochondrial import of ubiquitinated substrates d March5 directs degradation of import intermediates by proteasomes d USP30 KO mice have reduced abundance of the TOM complex

SUMMARYSpinocerebellar ataxia type 7 (SCA7) is a retinal-cerebellar degenerative disorder caused by CAG-polyglutamine (polyQ) repeat expansions in the ataxin-7 gene. As many SCA7 clinical phenotypes occur in mitochondrial disorders, and magnetic resonance spectroscopy of patients revealed altered energy metabolism, we considered a role for mitochondrial dysfunction. Studies of SCA7 mice uncovered marked impairments in oxygen consumption and respiratory exchange. When we examined cerebellar Purkinje cells in mice, we observed mitochondrial network abnormalities, with enlarged mitochondria upon ultrastructural analysis. We developed stem cell models from patients and created stem cell knockout rescue systems, documenting mitochondrial morphology defects, impaired oxidative metabolism, and reduced expression of nicotinamide adenine dinucleotide (NAD+) production enzymes in SCA7 models. We observed NAD+ reductions in mitochondria of SCA7 patient NPCs using ratiometric fluorescent sensors and documented alterations in tryptophan-kynurenine metabolism in patients. Our results indicate that mitochondrial dysfunction, stemming from decreased NAD+, is a defining feature of SCA7.