Effect of prior chronic contractile activity on mitochondrial function and apoptotic protein expression in denervated muscle

Abstract

O'Leary MF, Hood DA. Effect of prior chronic contractile activity on mitochondrial function and apoptotic protein expression in denervated muscle. J Appl Physiol 105: 114 -120, 2008. First published May 1, 2008 doi:10.1152/japplphysiol.00724.2007.-Skeletal muscle is highly adaptable in response to increases and decreases in contractile activity. The purpose of this study was to determine whether the preconditioning of skeletal muscle has a protective effect against subsequent denervation-induced apoptotic protein expression. To investigate this, we chronically stimulated the tibialis anterior and extensor digitorum longus muscles for 7 days (10 Hz, 3 h/day) before 7 days of denervation. Denervation reduced total cytochrome-c oxidase activity by 39%, which was likely a consequence of a decrease in subsarcolemmal (SS) mitochondria. This decrease in the SS subfraction was prevented by prior chronic stimulation and, as a result, maintained total mitochondrial content at control levels. The expression of Bax was elevated 2.2-fold by denervation, and prior chronic stimulation did not attenuate this increase. This produced a increase in the Bax-to-Bcl-2 ratio, indicating greater muscle apoptotic susceptibility. Denervation also decreased state 3 respiration in SS and intermyofibrillar mitochondria and elevated state 4 reactive oxygen species production within both mitochondrial subfractions. These changes were not prevented by prior chronic stimulation. Furthermore, the antioxidant protein MnSOD was also reduced by denervation, whereas Beclin-1 was markedly elevated. This suggests that autophagic cell death could also play a significant part in denervationinduced muscle atrophy. Thus, despite prior chronic stimulation, denervation increases the apoptotic susceptibility of skeletal muscle by altering the Bax-to-Bcl-2 ratio, by increasing reactive oxygen species production, and by reducing the expression of MnSOD. Whether a more extensive stimulation paradigm would be more effective in attenuating apoptosis before muscle disuse remains to be determined. mitochondrial biogenesis; muscle atrophy; reactive oxygen species; autophagy; protein degradation SKELETAL MUSCLE IS AN ADAPTABLE tissue that exhibits a remarkable range of plasticity in response to different levels of contractile activity (15). In particular, chronic contractile activity is known to alter the expression of a variety of proteins from the nuclear and mitochondrial genomes (15). These changes in protein expression result in an increase in mitochondrial volume and density (6, 16). In skeletal muscle, two distinct subfractions of mitochondria exist that are characterized by their anatomic localization. Subsarcolemmal (SS) mitochondria are located just beneath the sarcolemmal membrane, whereas intermyofibrillar (IMF) mitochondria are intertwined between skeletal muscle myofibrils (8). SS and IMF mitochondrial subfractions are significantly increased in response to chronic contractile activity. However, SS mitochondria are more sensitive to endurance training a...

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“…4 Furthermore, as the tendency toward sedentary lifestyles increases, and levels of physical activity continue to decrease in North American society, research into the effects of chronic muscle disuse will become increasingly important. Recent studies have shown that, in addition to decrements in skeletal muscle mass, chronic muscle disuse also decreases overall mitochondrial content and function, while stimulating an increase in mitochondrially-generated reactive oxygen species (ROS).…”

“…Recent studies have shown that, in addition to decrements in skeletal muscle mass, chronic muscle disuse also decreases overall mitochondrial content and function, while stimulating an increase in mitochondrially-generated reactive oxygen species (ROS). 4,5 These adaptive responses activate proapoptotic signaling pathways, and culminate in the fragmentation of nuclear DNA. 5 Prolonged periods of muscle disuse also increase the activity of the ubiquitinproteasome and autophagy degradation pathways.…”