Disconnecting Mitochondrial Content from Respiratory Chain Capacity in PGC-1-Deficient Skeletal Muscle
Glenn C. Rowe,
Ian S. Patten,
Zsuzsanna K. Zsengeller,
Riyad El-Khoury,
Mitsuharu Okutsu,
Sophia Bampoh,
Nicole Koulisis,
Caitlin Farrell,
Michael F. Hirshman,
Zhen Yan,
Laurie J. Goodyear,
Pierre Rustin,
Zolt Arany
Affiliations
Glenn C. Rowe
Cardiovascular Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
Ian S. Patten
Cardiovascular Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
Zsuzsanna K. Zsengeller
Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
Riyad El-Khoury
INSERM, UMR 676, Hôpital Robert Debré, 75019 Paris, France
Mitsuharu Okutsu
Center for Skeletal Muscle Research, Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
Sophia Bampoh
Cardiovascular Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
Nicole Koulisis
Cardiovascular Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
Caitlin Farrell
Cardiovascular Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
Michael F. Hirshman
Joslin Diabetes Center, Boston, MA 02215, USA
Zhen Yan
Center for Skeletal Muscle Research, Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
Laurie J. Goodyear
Joslin Diabetes Center, Boston, MA 02215, USA
Pierre Rustin
INSERM, UMR 676, Hôpital Robert Debré, 75019 Paris, France
Zolt Arany
Cardiovascular Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA
The transcriptional coactivators PGC-1α and PGC-1β are widely thought to be required for mitochondrial biogenesis and fiber typing in skeletal muscle. Here, we show that mice lacking both PGC-1s in myocytes do indeed have profoundly deficient mitochondrial respiration but, surprisingly, have preserved mitochondrial content, isolated muscle contraction capacity, fiber-type composition, in-cage ambulation, and voluntary running capacity. Most of these findings are recapitulated in cell culture and, thus, are cell autonomous. Functional electron microscopy reveals normal cristae density with decreased cytochrome oxidase activity. These data lead to the following surprising conclusions: (1) PGC-1s are in fact dispensable for baseline muscle function, mitochondrial content, and fiber typing, (2) endurance fatigue at low workloads is not limited by muscle mitochondrial capacity, and (3) mitochondrial content and cristae density can be dissociated from respiratory capacity.
