Diabetes is associated with decreased muscle strength and energy production. There is a strong association between muscle insulin resistance and mitochondrial abnormalities, but cause/effect remains hotly debated. Recently, we showed that insulin receptor (IR) and IGF-1 receptor (IGF1R) signaling controls muscle atrophy by FoxO1/3/4-dependent regulation of autophagy. To directly test the roles of IR, IGF1R, and FoxO signaling on muscle metabolism and mitochondrial autophagy (mitophagy) we measured mitochondrial function in mice lacking IR (M-IR-/-), both IR/IGF1R (MIGIRKO), or IR/IGF1R/FoxO1/3/4 (QKO) in muscle. RNA seq analysis revealed decreases in multiple mitochondrial pathways from M-IR-/- and MIGIRKO muscle, including OXPHOS. Respiratory capacity and ATP production were decreased in mitochondria and soleus fibers isolated from M-IR-/- and MIGIRKO mice using complex I substrates. These decreases in OXPHOS and mitochondrial function were normalized when FoxOs were deleted in QKO mice. MIGIRKO muscle showed decreased PINK1 (mitophagy protein) and increased LC3II/I ratio, indicating changes in respiration and mitophagy occurred together. To determine if this was cell autonomous, C2C12 myotubes were pre-treated with insulin and/or CCCP (an uncoupler and mitophagy-inducer), and assayed for respiration. Insulin increased respiration and PINK1 levels after 24 hours. Four hour CCCP pre-treatment reduced basal respiration and increased LC3II/I which were partially, but significantly, rescued with insulin in C2C12 myotubes. PINK1 was also decreased in primary myotubes with acute deletion of IR/IGF1R. Thus, loss of IR/IGFR signaling in skeletal muscle directly reduces mitochondrial respiratory capacity and alters mitophagy, which is regulated by FoxO transcription factors.


G. Bhardwaj: None. C.M. Penniman: None. P.A. Suarez Beltran: None. C.M. Foster: None. B.T. O'Neill: None.

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