Abstract
Aging triggers several abnormalities in muscle glycolytic fibers including increased proteolysis, reactive oxygen species (ROS) production and apoptosis. Since the mitochondria are the main site of substrate oxidation, ROS production and programmed cell death, we tried to know whether the cellular disorders encountered in sarcopenia are due to abnormal mitochondrial functioning. Gastrocnemius mitochondria were extracted from adult (6 months) and aged (21 months) male Wistar rats. Respiration parameters, opening of the permeability transition pore and ROS production, with either glutamate (amino acid metabolism) or pyruvate (glucose metabolism) as a respiration substrate, were evaluated at different matrix calcium concentrations. Pyruvate dehydrogenase and respiratory complex activities as well as their contents measured by Western blotting analysis were determined. Furthermore, the fatty acid profile of mitochondrial phospholipids was also measured. At physiological calcium concentration, state III respiration rate was lowered by aging in pyruvate conditions (-22%), but not with glutamate. The reduction of pyruvate oxidation resulted from a calcium-dependent inactivation of the pyruvate dehydrogenase system and could provide for the well-known proteolysis encountered during sarcopenia. Matrix calcium loading and aging increased ROS production. They also reduced the oxidative phosphorylation. This was associated with lower calcium retention capacities, suggesting that sarcopenic fibers are more prone to programmed cell death. Aging was also associated with a reduced mitochondrial superoxide dismutase activity, which does not intervene in toxic ROS overproduction but could explain the lower calcium retention capacities. Despite a lower content, cytochrome c oxidase displayed an increased activity associated with an increased n-6/n-3 polyunsaturated fatty acid ratio of mitochondrial phospholipids. In conclusion, we propose that mitochondria obtained from aged muscle fibers display several functional abnormalities explaining the increased proteolysis, ROS overproduction and vulnerability to apoptosis exhibited by sarcopenic muscle. These changes appear to be related to modifications of the fatty acid profile of mitochondrial lipids.
Highlights
Between 20 and 80 years old, individuals lose approximately 40% of the skeletal muscle mass of their legs (Wanagat et al, 2001)
It makes them overproduce reactive oxygen species (ROS) (Ji, 2002; Capel et al, 2004; Fulle et al, 2004). It destroys them through apoptosis (Pollack & Leeuwenburgh, 2001; Pollack et al, 2002). All these processes could result from abnormal mitochondrial functioning, since the mitochondria are the main site of substrate oxidation, ROS production and the initiation of programmed cell death
The purpose of this study was to evaluate the aging-related changes in mitochondrial functioning to find out if they can partly explain the abnormalities observed in the sarcopenic gastrocnemius
Summary
Between 20 and 80 years old, individuals lose approximately 40% of the skeletal muscle mass of their legs (Wanagat et al, 2001). Sarcopenia mainly affects glycolytic fibers (Thompson, 1994), causing atrophy (Reynolds et al, 2002) via increased proteolytic activity (Yarasheski, 2003; Zinna & Yarasheski, 2003). It makes them overproduce reactive oxygen species (ROS) (Ji, 2002; Capel et al, 2004; Fulle et al, 2004). It destroys them through apoptosis (Pollack & Leeuwenburgh, 2001; Pollack et al, 2002). All these processes could result from abnormal mitochondrial functioning, since the mitochondria are the main site of substrate oxidation, ROS production and the initiation of programmed cell death
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