| Autor: |
Neyroud D; Department of Physical Therapy, University of Florida, Gainesville, USA.; Myology Institute, University of Florida, Gainesville, USA.; Institute of Sports Sciences, University of Lausanne, Lausanne, Switzerland., Laitano O; Myology Institute, University of Florida, Gainesville, USA.; Department of Applied Physiology & Kinesiology, University of Florida, Gainesville, USA., Daguspta A; Department of Anatomy, Cell Biology and Physiology, Indiana university school of medicine, Indianapolis, Indiana.; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota., Lopez C; Department of Physical Therapy, University of Florida, Gainesville, USA.; Myology Institute, University of Florida, Gainesville, USA., Schmitt RE; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota., Schneider JZ; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota., Hammers DW; Myology Institute, University of Florida, Gainesville, USA.; Department of Pharmacology and Therapeutics, University of Florida, Gainesville, USA., Sweeney HL; Myology Institute, University of Florida, Gainesville, USA.; Department of Pharmacology and Therapeutics, University of Florida, Gainesville, USA., Walter GA; Myology Institute, University of Florida, Gainesville, USA.; Department of Physiology and Aging, University of Florida, Gainesville, USA., Doles J; Department of Anatomy, Cell Biology and Physiology, Indiana university school of medicine, Indianapolis, Indiana.; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota., Judge SM; Department of Physical Therapy, University of Florida, Gainesville, USA.; Myology Institute, University of Florida, Gainesville, USA., Judge AR; Department of Physical Therapy, University of Florida, Gainesville, USA.; Myology Institute, University of Florida, Gainesville, USA. |
| Abstrakt: |
Cancer-induced muscle wasting reduces quality of life, complicates or precludes cancer treatments, and predicts early mortality. Herein, we investigated the requirement of the muscle-specific E3 ubiquitin ligase, MuRF1, for muscle wasting induced by pancreatic cancer. Murine pancreatic cancer (KPC) cells, or saline, were injected into the pancreas of WT and MuRF1-/- mice, and tissues analyzed throughout tumor progression. KPC tumors induced progressive wasting of skeletal muscle and systemic metabolic reprogramming in WT mice, but not MuRF1-/- mice. KPC tumors from MuRF1-/- mice also grew slower, and showed an accumulation of metabolites normally depleted by rapidly growing tumors. Mechanistically, MuRF1 was necessary for the KPC-induced increases in cytoskeletal and muscle contractile protein ubiquitination, and the depression of proteins that support protein synthesis. Together, these data demonstrate that MuRF1 is required for KPC-induced skeletal muscle wasting, whose deletion reprograms the systemic and tumor metabolome and delays tumor growth. |
