PPARa‐ATGL pathway improves muscle mitochondrial metabolism: implication in aging

Adipose triglyceride lipase (ATGL) maintains an optimum mitochondrial function putatively by generating cognate ligands for peroxisome proliferator-activated receptor α (PPARα), which, together with PPARγ coactivator-1α (PGC1α), regulate muscle mitochondrial biogenesis. However, the cross-talk between ATGL and PPARα in skeletal muscle mitochondrial metabolism and its implication in chronological aging is poorly understood. The role of ATGL in muscle mitochondrial metabolism was studied by overexpressing and depleting the geneandstudyingitsdownstreameffect in cultured myotubes and in murine skeletal muscle. We found that PPARα directly induces ATGL expression during myogenesis. Overexpression of ATGL significantly enhanced while depletion of ATGL attenuated mitochondrial oxidative phosphorylation and fatty acid oxidation without alteration in mitochondrial content, and it rendered PPARα and PGC1α redundant in promoting mitochondrial oxidative function. However, ATGL did not alter PPAR-dependent lipid accumulation and insulin sensitivity. In middleaged rats, ATGL expression was higher and correlated with PPARα expression and sustained fatty acid oxidation in oxidative soleus muscle. Fenofibrate feeding further induced ATGL expression selectively in this muscle compartment. These findings illustrate that PPARα and ATGL constitute a regulatory pathway in skeletal muscle, suggesting their role as a mitochondrial metabolic reserve.—Biswas, D., Ghosh, M., Kumar, S., Chakrabarti, P. PPARα-ATGL pathway improves muscle mitochondrial metabolism: implication in aging. FASEB J. 30, 3822–3834 (2016) www.fasebj.org