Insulin and IGF-1 receptors regulate complex I-dependent mitochondrial bioenergetics and supercomplexes via FoxOs in...

Area of Science:

• Mitochondrial biology
• Endocrinology
• Muscle physiology

Background:

• Diabetes is characterized by decreased skeletal muscle strength and mitochondrial dysfunction.
• Insulin and IGF-1 signaling pathways, via insulin receptor (IR) and IGF-1 receptor (IGF1R), normally suppress forkhead box O (FoxO) transcription factors to maintain muscle mass.
• The coordinated role of FoxO activation in muscle atrophy and mitochondrial dysfunction in diabetes remains unclear.

Purpose of the Study:

• To investigate the role of FoxO transcription factors in mediating mitochondrial dysfunction and muscle atrophy in the context of diabetes and impaired insulin/IGF-1 signaling.
• To determine if FoxO activation contributes to decreased mitochondrial respiration and complex I activity in diabetic muscle.
• To elucidate the molecular mechanisms by which insulin/IGF-1 signaling and FoxO influence mitochondrial function in skeletal muscle.

Main Methods:

• Utilized streptozotocin (STZ)-induced diabetes model in mice.
• Generated muscle-specific knockout (KO) models including triple KO for FoxO1, -3, and -4 (M-FoxO TKO) and quintuple KO for IR, IGF1R, and FoxO1, -3, -4 (M-QKO).
• Employed acute tamoxifen-inducible deletion of IR and IGF1R in muscle.
• Assessed mitochondrial respiration, complex I activity, ATP production, reactive oxygen species (ROS) generation, autophagy, mitophagy, and gene expression via RNA-Seq.

Main Results:

• STZ-induced diabetes decreased mitochondrial respiration and complex I activity, which were restored in M-FoxO TKO mice.
• Muscle-specific deletion of IR or combined IR/IGF1R impaired mitochondrial respiration, reduced ATP, and increased ROS, but these defects were absent in M-QKO mice.
• Acute deletion of IR/IGF1R decreased pyruvate respiration, complex I activity, and supercomplex assembly; autophagy increased, but mitophagy did not.
• RNA-Seq revealed decreased expression of complex I core subunits in diabetic and MIGIRKO muscle, an effect prevented by FoxO deletion.

Conclusions:

• FoxO transcription factors play a critical role in mediating mitochondrial dysfunction, specifically impaired complex I respiration and supercomplex assembly, in the context of diabetes and loss of insulin/IGF-1 signaling in muscle.
• Insulin-deficient diabetes or impaired insulin/IGF-1 action in muscle leads to mitochondrial defects, partly through FoxO-mediated repression of complex I subunit expression.
• Targeting FoxO pathways may offer a therapeutic strategy to combat muscle atrophy and mitochondrial dysfunction associated with diabetes.