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Potential molecular mechanisms underlying muscle fatigue mediated by reactive oxygen and nitrogen species.

Debold EP - Front Physiol (2015)

Bottom Line: Much of the research effort has focused on how elevated levels of the metabolites of ATP hydrolysis might inhibit the function of the contractile proteins.Based on this approach at least two areas are beginning emerge as potentially important sites, the regulatory protein troponin and the actin binding region of myosin.This work may also have implications beyond muscle fatigue as ROS/RNS mediated protein modifications are also thought to play a role in the loss of muscle function with aging and in some acute pathologies like cardiac arrest and ischemia.

View Article: PubMed Central - PubMed

Affiliation: Department of Kinesiology, University of Massachusetts Amherst, MA, USA.

ABSTRACT
Intense contractile activity causes a dramatic decline in the force and velocity generating capacity of skeletal muscle within a few minutes, a phenomenon that characterizes fatigue. Much of the research effort has focused on how elevated levels of the metabolites of ATP hydrolysis might inhibit the function of the contractile proteins. However, there is now growing evidence that elevated levels of reactive oxygen and nitrogen species (ROS/RNS), which also accumulate in the myoplasm during fatigue, also play a causative role in this type of fatigue. The most compelling evidence comes from observations demonstrating that pre-treatment of intact muscle with a ROS scavenger can significantly attenuate the development of fatigue. A clear advantage of this line of inquiry is that the molecular targets and protein modifications of some of the ROS scavengers are well-characterized enabling researchers to begin to identify potential regions and even specific amino acid residues modified during fatigue. Combining this knowledge with assessments of contractile properties from the whole muscle level down to the dynamic motions within specific contractile proteins enable the linking of the structural modifications to the functional impacts, using advanced chemical and biophysical techniques. Based on this approach at least two areas are beginning emerge as potentially important sites, the regulatory protein troponin and the actin binding region of myosin. This review highlights some of these recent efforts which have the potential to offer uniquely precise information on the underlying molecular basis of fatigue. This work may also have implications beyond muscle fatigue as ROS/RNS mediated protein modifications are also thought to play a role in the loss of muscle function with aging and in some acute pathologies like cardiac arrest and ischemia.

No MeSH data available.


Related in: MedlinePlus

Effect of reactive oxygen species scavengers on fatigue. (A) Effect of pretreatment with ROS scavenger, N-acetylcysteine (circles) vs. control (squares) on the fatigue profile of the tibialis anterior muscle in humans stimulated at 10 Hz with a surface electrode. The drop in force was significant under both conditions but the force was greater with N-acetylcysteine treatment. Reprinted from Reid et al. (1994) with rights and permission from American Society for Clinical Investigation. (B) Effect of the N-acetylcysteine on the development of diaphragm fatigue in an anesthetized intact rabbit preparation. Reprinted from Shindoh et al. (1990) with permission. (C) Effect of N-acetylcysteine on the development of fatigue in isolated mouse extensor digitorum longus muscle. Reprinted from Katz et al. (2014) with permission. *, ** and *** indicate significantly different from corresponding control value (open circles) at p < 0.05, p < 0.01, and p < 0.001 respectively.
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Figure 1: Effect of reactive oxygen species scavengers on fatigue. (A) Effect of pretreatment with ROS scavenger, N-acetylcysteine (circles) vs. control (squares) on the fatigue profile of the tibialis anterior muscle in humans stimulated at 10 Hz with a surface electrode. The drop in force was significant under both conditions but the force was greater with N-acetylcysteine treatment. Reprinted from Reid et al. (1994) with rights and permission from American Society for Clinical Investigation. (B) Effect of the N-acetylcysteine on the development of diaphragm fatigue in an anesthetized intact rabbit preparation. Reprinted from Shindoh et al. (1990) with permission. (C) Effect of N-acetylcysteine on the development of fatigue in isolated mouse extensor digitorum longus muscle. Reprinted from Katz et al. (2014) with permission. *, ** and *** indicate significantly different from corresponding control value (open circles) at p < 0.05, p < 0.01, and p < 0.001 respectively.

Mentions: Some of the most compelling evidence comes from the observation that pre-treatment with exogenous ROS scavengers attenuates the rate and extent of fatigue in intact muscle (see Figure 1). While this is most pronounced in isolated muscle preparations (Shindoh et al., 1990; Moopanar and Allen, 2005, 2006) where the ex vivo nature of the preparations might augment the level of ROS (Halliwell, 2014), it has also been observed in exercising humans (Reid et al., 1994; Medved et al., 2004; Ferreira et al., 2011; Slattery et al., 2014). The preventative effect of ROS scavengers is most obvious in humans when fatigue is induced with low stimulation frequencies (Reid et al., 1994), but it is also dependent on the variant of ROS scavenger (Hernández et al., 2012). Thus, there is evidence that ROS/RNS scavengers can delay fatigue and that the accumulation of ROS is linked to the onset and extent of fatigue, which provide compelling support for a causative role. The molecular mechanisms underlying these effects remain unclear but in the last 5–10 years several research groups have made significant advances that have identified specific contractile proteins modified by ROS/RNS and their impact on molecular function (Callahan et al., 2001; Moopanar and Allen, 2005, 2006; Prochniewicz et al., 2008; Dutka et al., 2011; Klein et al., 2011; Mollica et al., 2012; Moen et al., 2014b; Cheng et al., 2015). This review focuses on these recent efforts that highlight the potential molecular mechanism of ROS/RNS mediated fatigue.


Potential molecular mechanisms underlying muscle fatigue mediated by reactive oxygen and nitrogen species.

Debold EP - Front Physiol (2015)

Effect of reactive oxygen species scavengers on fatigue. (A) Effect of pretreatment with ROS scavenger, N-acetylcysteine (circles) vs. control (squares) on the fatigue profile of the tibialis anterior muscle in humans stimulated at 10 Hz with a surface electrode. The drop in force was significant under both conditions but the force was greater with N-acetylcysteine treatment. Reprinted from Reid et al. (1994) with rights and permission from American Society for Clinical Investigation. (B) Effect of the N-acetylcysteine on the development of diaphragm fatigue in an anesthetized intact rabbit preparation. Reprinted from Shindoh et al. (1990) with permission. (C) Effect of N-acetylcysteine on the development of fatigue in isolated mouse extensor digitorum longus muscle. Reprinted from Katz et al. (2014) with permission. *, ** and *** indicate significantly different from corresponding control value (open circles) at p < 0.05, p < 0.01, and p < 0.001 respectively.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4555024&req=5

Figure 1: Effect of reactive oxygen species scavengers on fatigue. (A) Effect of pretreatment with ROS scavenger, N-acetylcysteine (circles) vs. control (squares) on the fatigue profile of the tibialis anterior muscle in humans stimulated at 10 Hz with a surface electrode. The drop in force was significant under both conditions but the force was greater with N-acetylcysteine treatment. Reprinted from Reid et al. (1994) with rights and permission from American Society for Clinical Investigation. (B) Effect of the N-acetylcysteine on the development of diaphragm fatigue in an anesthetized intact rabbit preparation. Reprinted from Shindoh et al. (1990) with permission. (C) Effect of N-acetylcysteine on the development of fatigue in isolated mouse extensor digitorum longus muscle. Reprinted from Katz et al. (2014) with permission. *, ** and *** indicate significantly different from corresponding control value (open circles) at p < 0.05, p < 0.01, and p < 0.001 respectively.
Mentions: Some of the most compelling evidence comes from the observation that pre-treatment with exogenous ROS scavengers attenuates the rate and extent of fatigue in intact muscle (see Figure 1). While this is most pronounced in isolated muscle preparations (Shindoh et al., 1990; Moopanar and Allen, 2005, 2006) where the ex vivo nature of the preparations might augment the level of ROS (Halliwell, 2014), it has also been observed in exercising humans (Reid et al., 1994; Medved et al., 2004; Ferreira et al., 2011; Slattery et al., 2014). The preventative effect of ROS scavengers is most obvious in humans when fatigue is induced with low stimulation frequencies (Reid et al., 1994), but it is also dependent on the variant of ROS scavenger (Hernández et al., 2012). Thus, there is evidence that ROS/RNS scavengers can delay fatigue and that the accumulation of ROS is linked to the onset and extent of fatigue, which provide compelling support for a causative role. The molecular mechanisms underlying these effects remain unclear but in the last 5–10 years several research groups have made significant advances that have identified specific contractile proteins modified by ROS/RNS and their impact on molecular function (Callahan et al., 2001; Moopanar and Allen, 2005, 2006; Prochniewicz et al., 2008; Dutka et al., 2011; Klein et al., 2011; Mollica et al., 2012; Moen et al., 2014b; Cheng et al., 2015). This review focuses on these recent efforts that highlight the potential molecular mechanism of ROS/RNS mediated fatigue.

Bottom Line: Much of the research effort has focused on how elevated levels of the metabolites of ATP hydrolysis might inhibit the function of the contractile proteins.Based on this approach at least two areas are beginning emerge as potentially important sites, the regulatory protein troponin and the actin binding region of myosin.This work may also have implications beyond muscle fatigue as ROS/RNS mediated protein modifications are also thought to play a role in the loss of muscle function with aging and in some acute pathologies like cardiac arrest and ischemia.

View Article: PubMed Central - PubMed

Affiliation: Department of Kinesiology, University of Massachusetts Amherst, MA, USA.

ABSTRACT
Intense contractile activity causes a dramatic decline in the force and velocity generating capacity of skeletal muscle within a few minutes, a phenomenon that characterizes fatigue. Much of the research effort has focused on how elevated levels of the metabolites of ATP hydrolysis might inhibit the function of the contractile proteins. However, there is now growing evidence that elevated levels of reactive oxygen and nitrogen species (ROS/RNS), which also accumulate in the myoplasm during fatigue, also play a causative role in this type of fatigue. The most compelling evidence comes from observations demonstrating that pre-treatment of intact muscle with a ROS scavenger can significantly attenuate the development of fatigue. A clear advantage of this line of inquiry is that the molecular targets and protein modifications of some of the ROS scavengers are well-characterized enabling researchers to begin to identify potential regions and even specific amino acid residues modified during fatigue. Combining this knowledge with assessments of contractile properties from the whole muscle level down to the dynamic motions within specific contractile proteins enable the linking of the structural modifications to the functional impacts, using advanced chemical and biophysical techniques. Based on this approach at least two areas are beginning emerge as potentially important sites, the regulatory protein troponin and the actin binding region of myosin. This review highlights some of these recent efforts which have the potential to offer uniquely precise information on the underlying molecular basis of fatigue. This work may also have implications beyond muscle fatigue as ROS/RNS mediated protein modifications are also thought to play a role in the loss of muscle function with aging and in some acute pathologies like cardiac arrest and ischemia.

No MeSH data available.


Related in: MedlinePlus