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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

ROS mediated fatigue and Ca++-sensitivity. Force-calcium relation plotted during fatigue of intact mouse flexor brevis muscle fibers stimulated at 100 Hz, at 37°C. Force expressed relative to rested value under control conditions. Fatigue under control conditions produced a strong rightward shift in the relation and depressed maximal force. Maximal force but not Ca++-sensitivity was restored with caffeine. Treatment with dithiothreitol (DTT) restored Ca++-sensitivity. Reprinted from Moopanar and Allen (2006) with permission from John Wiley and Sons publishing company.
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Figure 2: ROS mediated fatigue and Ca++-sensitivity. Force-calcium relation plotted during fatigue of intact mouse flexor brevis muscle fibers stimulated at 100 Hz, at 37°C. Force expressed relative to rested value under control conditions. Fatigue under control conditions produced a strong rightward shift in the relation and depressed maximal force. Maximal force but not Ca++-sensitivity was restored with caffeine. Treatment with dithiothreitol (DTT) restored Ca++-sensitivity. Reprinted from Moopanar and Allen (2006) with permission from John Wiley and Sons publishing company.

Mentions: However, these findings stand in stark contrast to the results from intact muscle preparations which have consistently observed that ROS decreases Ca++-sensitivity while exerting minimal effects on maximal isometric force (Andrade et al., 1998, 2001; Moopanar and Allen, 2005, 2006). For example, elevated levels of H2O2 produced a pronounced rightward shift in the force-calcium relation in intact muscle fibers without affecting the intracellular Ca++ concentration (Figure 2), suggesting that the H2O2 decreased the Ca++-sensitivity of the myofilaments (Andrade et al., 1998). This work was confirmed and extended in a more recent where intact muscle was fatigued in the presence of DTT (Moopanar and Allen, 2006). In this study living mouse fast muscle fibers were stimulated to fatigue while simultaneously measuring isometric force and intracellular levels of Ca++, enabling the ability to directly determine the force-calcium relationship in an intact fiber during fatigue. Consistent with prior experiments in intact muscle, Ca++ release was compromised by fatigue but this was not reversed by DTT, indicating no role for ROS. Ca++-sensitivity however was depressed and was fully reversed by DTT. While subsequent findings suggested that iron leeching off the stimulating electrode in these experiments likely drove the ROS concentration higher than originally reported (Reardon and Allen, 2009a,b) it remains clear that elevated levels of ROS mediated the depressive effects on force. Therefore, these findings suggest that elevated levels of ROS decrease the Ca++-sensitivity of the myofilaments and that this may be the primary mechanism through which ROS induces fatigue in intact muscle.


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

Debold EP - Front Physiol (2015)

ROS mediated fatigue and Ca++-sensitivity. Force-calcium relation plotted during fatigue of intact mouse flexor brevis muscle fibers stimulated at 100 Hz, at 37°C. Force expressed relative to rested value under control conditions. Fatigue under control conditions produced a strong rightward shift in the relation and depressed maximal force. Maximal force but not Ca++-sensitivity was restored with caffeine. Treatment with dithiothreitol (DTT) restored Ca++-sensitivity. Reprinted from Moopanar and Allen (2006) with permission from John Wiley and Sons publishing company.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 2: ROS mediated fatigue and Ca++-sensitivity. Force-calcium relation plotted during fatigue of intact mouse flexor brevis muscle fibers stimulated at 100 Hz, at 37°C. Force expressed relative to rested value under control conditions. Fatigue under control conditions produced a strong rightward shift in the relation and depressed maximal force. Maximal force but not Ca++-sensitivity was restored with caffeine. Treatment with dithiothreitol (DTT) restored Ca++-sensitivity. Reprinted from Moopanar and Allen (2006) with permission from John Wiley and Sons publishing company.
Mentions: However, these findings stand in stark contrast to the results from intact muscle preparations which have consistently observed that ROS decreases Ca++-sensitivity while exerting minimal effects on maximal isometric force (Andrade et al., 1998, 2001; Moopanar and Allen, 2005, 2006). For example, elevated levels of H2O2 produced a pronounced rightward shift in the force-calcium relation in intact muscle fibers without affecting the intracellular Ca++ concentration (Figure 2), suggesting that the H2O2 decreased the Ca++-sensitivity of the myofilaments (Andrade et al., 1998). This work was confirmed and extended in a more recent where intact muscle was fatigued in the presence of DTT (Moopanar and Allen, 2006). In this study living mouse fast muscle fibers were stimulated to fatigue while simultaneously measuring isometric force and intracellular levels of Ca++, enabling the ability to directly determine the force-calcium relationship in an intact fiber during fatigue. Consistent with prior experiments in intact muscle, Ca++ release was compromised by fatigue but this was not reversed by DTT, indicating no role for ROS. Ca++-sensitivity however was depressed and was fully reversed by DTT. While subsequent findings suggested that iron leeching off the stimulating electrode in these experiments likely drove the ROS concentration higher than originally reported (Reardon and Allen, 2009a,b) it remains clear that elevated levels of ROS mediated the depressive effects on force. Therefore, these findings suggest that elevated levels of ROS decrease the Ca++-sensitivity of the myofilaments and that this may be the primary mechanism through which ROS induces fatigue in intact muscle.

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