Age-related activation of mitochondrial caspase-independent apoptotic signaling in rat gastrocnemius muscle.
Mitochondria-mediated apoptosis represents a central process driving age-related muscle loss. However, the temporal relation between mitochondrial apoptotic signaling and sarcopenia as well as the regulation of release of pro-apoptotic factors from the mitochondria has not been elucidated. In this study, we investigated mitochondrial apoptotic signaling in skeletal muscle of rats across a wide age range. We also investigated whether mitochondrial-driven apoptosis was accompanied by changes in the expression of Bcl-2 proteins and components of the mitochondrial permeability transition pore (mPTP). Analyses were performed on gastrocnemius muscle of 8-, 18-, 29- and 37-month-old male Fischer344 x Brown Norway rats (9 per group). Muscle weight declined progressively with advancing age, concomitant with increased apoptotic DNA fragmentation. Cytosolic and nuclear levels of apoptosis inducing factor (AIF) and endonuclease G (EndoG) increased in old and senescent animals. In contrast, cytosolic levels of cytochrome c were unchanged with age. Mitochondrial Bcl-2, Bax and Bid increased dramatically in 37-month-old rats, with no changes in the Bax/Bcl-2 ratio in any of the age groups. Finally, expression of cyclophilin D (CyPD) was enhanced at very old age. Our findings indicate that the mitochondrial caspase-independent apoptotic pathway may play a more prominent role in skeletal muscle loss than caspase-mediated apoptosis.
Marzetti
Emanuele
E
Department of Aging and Geriatric Research, Institute on Aging, Division of Biology of Aging, University of Florida, Gainesville, FL 32610-0143, USA. emarzetti@aging.ufl.edu
Wohlgemuth
Stephanie Eva
SE
Lees
Hazel Anne
HA
Chung
Hae-Young
HY
Giovannini
Silvia
S
Leeuwenburgh
Christiaan
C
D000375:Aging / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000378:metabolism / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D008297:Male; D008928:Mitochondria / Q000201:enzymology / Q000502:physiology*; D033681:Mitochondrial Membrane Transport Proteins / Q000502:physiology; D051336:Mitochondrial Membranes / Q000201:enzymology / Q000502:physiology; D000083162:Mitochondrial Permeability Transition Pore; D018482:Muscle, Skeletal / Q000166:cytology* / Q000201:enzymology / Q000502:physiology*; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D015398:Signal Transduction / Q000502:physiology*
D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D020169:Caspases