Rapamycin doses sufficient to extend lifespan do not compromise muscle mitochondrial content or endurance.
Rapamycin extends lifespan in mice, but can have a number of undesirable effects that may ultimately limit its utility in humans. The canonical target of rapamycin, and the one thought to account for its effects on lifespan, is the mammalian/mechanistic target of rapamycin, complex 1 (mTORC1). We have previously shown that at least some of the detrimental side effects of rapamycin are due to "off target" disruption of mTORC2, suggesting they could be avoided by more specific targeting of mTORC1. However, mTORC1 inhibitionper se can reduce the mRNA expression of mitochondrial genes and compromise the function of mitochondria in cultured muscle cells, implying that defects in bioenergetics might be an unavoidable consequence of targeting mTORC1 in vivo. Therefore, we tested whether rapamycin, at the same doses used to extend lifespan, affects mitochondrial function in skeletal muscle. While mitochondrial transcripts were decreased, particularly in the highly oxidative soleus muscle, we found no consistent change in mitochondrial DNA or protein levels. In agreement with the lack of change in mitochondrial components, rapamycin-treated mice had endurance equivalent to that of untreated controls, and isolated, permeabilized muscle fibers displayed similar rates of oxygen consumption. We conclude that the doses of rapamycin required to extend life do not cause overt mitochondrial dysfunction in skeletal muscle.
State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
Lan
L
Ye
Anne L
AL
Widlund
Carrie A
CA
Sims
Dudley W
DW
Lamming
Yuxia
Y
Guan
James G
JG
Davis
David M
DM
Sabatini
David E
DE
Harrison
Ole
O
Vang
Joseph A
JA
Baur
D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008931:Mitochondria, Muscle / Q000187:drug effects* / Q000502:physiology; D009043:Motor Activity / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000502:physiology; D010807:Physical Endurance / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*
D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D020123:Sirolimus