PGC-1alpha integrates insulin signaling, mitochondrial regulation, and bioenergetic function in skeletal muscle.
The pathophysiology underlying mitochondrial dysfunction in insulin-resistant skeletal muscle is incompletely characterized. To further delineate this we investigated the interaction between insulin signaling, mitochondrial regulation, and function in C2C12 myotubes and in skeletal muscle. In myotubes elevated insulin and glucose disrupt insulin signaling, mitochondrial biogenesis, and mitochondrial bioenergetics. The insulin-sensitizing thiazolidinedione pioglitazone restores these perturbations in parallel with induction of the mitochondrial biogenesis regulator PGC-1alpha. Overexpression of PGC-1alpha rescues insulin signaling and mitochondrial bioenergetics, and its silencing concordantly disrupts insulin signaling and mitochondrial bioenergetics. In primary skeletal myoblasts pioglitazone also up-regulates PGC-1alpha expression and restores the insulin-resistant mitochondrial bioenergetic profile. In parallel, pioglitazone up-regulates PGC-1alpha in db/db mouse skeletal muscle. Interestingly, the small interfering RNA knockdown of the insulin receptor in C2C12 myotubes down-regulates PGC-1alpha and attenuates mitochondrial bioenergetics. Concordantly, mitochondrial bioenergetics are blunted in insulin receptor knock-out mouse-derived skeletal myoblasts. Taken together these data demonstrate that elevated glucose and insulin impairs and pioglitazone restores skeletal myotube insulin signaling, mitochondrial regulation, and bioenergetics. Pioglitazone functions in part via the induction of PGC-1alpha. Moreover, PGC-1alpha is identified as a bidirectional regulatory link integrating insulin-signaling and mitochondrial homeostasis in skeletal muscle.
Pagel-Langenickel
Ines
I
Translational Medicine Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892-1454, USA.
Bao
Jianjun
J
Joseph
Joshua J
JJ
Schwartz
Daniel R
DR
Mantell
Benjamin S
BS
Xu
Xiuli
X
Raghavachari
Nalini
N
Sack
Michael N
MN
D000818:Animals; D002460:Cell Line; D004272:DNA, Mitochondrial / Q000235:genetics; D004734:Energy Metabolism; D005786:Gene Expression Regulation; D007328:Insulin / Q000502:physiology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000502:physiology*; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D010101:Oxygen Consumption; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D000077205:Pioglitazone; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D011972:Receptor, Insulin / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D045162:Thiazolidinediones / Q000494:pharmacology; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors
D004272:DNA, Mitochondrial; D007328:Insulin; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D045162:Thiazolidinediones; D015534:Trans-Activators; D014157:Transcription Factors; D012313:RNA; D011972:Receptor, Insulin; D000077205:Pioglitazone