Eliminating Nox2 reactive oxygen species production protects dystrophic skeletal muscle from pathological calcium influx assessed <i>in vivo</i> by manganese‐enhanced magnetic resonance imaging

Loehr, James A.; Stinnett, Gary; Hernández‐Rivera, Mayra; Roten, Wesley T.; Wilson, Lon J.; Pautler, Robia G.; Rodney, George G.

doi:10.1113/jp272907

Cited by 19 publications

(26 citation statements)

References 61 publications

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“…The antioxidant NAC protects mdx muscle from ECCinduced force loss in a muscle length change-dependent manner ECC-induced force loss of isolated mdx EDL muscle is associated with oxidative stress [9,36]. We have previously shown that addition of NAC partially protects mdx EDL muscle from losing force from ECCs of a 10% length change [9], and here we confirmed this result (Fig.…”

Section: Sarcolemmal Damage Is Associated With the Muscle Length Chansupporting

confidence: 88%

Mechanical factors tune the sensitivity of mdx muscle to eccentric strength loss and its protection by antioxidant and calcium modulators

et al. 2020

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Background: Dystrophin deficiency sensitizes skeletal muscle of mice to eccentric contraction (ECC)-induced strength loss. ECC protocols distinguish dystrophin-deficient from healthy, wild type muscle, and test the efficacy of therapeutics for Duchenne muscular dystrophy (DMD). However, given the large lab-to-lab variability in ECCinduced strength loss of dystrophin-deficient mouse skeletal muscle (10-95%), mechanical factors of the contraction likely impact the degree of loss. Therefore, the purpose of this study was to evaluate the extent to which mechanical variables impact sensitivity of dystrophin-deficient mouse skeletal muscle to ECC. Methods: We completed ex vivo and in vivo muscle preparations of the dystrophin-deficient mdx mouse and designed ECC protocols within physiological ranges of contractile parameters (length change, velocity, contraction duration, and stimulation frequencies). To determine whether these contractile parameters affected known factors associated with ECC-induced strength loss, we measured sarcolemmal damage after ECC as well as strength loss in the presence of the antioxidant N-acetylcysteine (NAC) and small molecule calcium modulators that increase SERCA activity (DS-11966966 and CDN1163) or lower calcium leak from the ryanodine receptor (Chloroxine and Myricetin). Results: The magnitude of length change, work, and stimulation duration ex vivo and in vivo of an ECC were the most important determinants of strength loss in mdx muscle. Passive lengthening and submaximal stimulations did not induce strength loss. We further showed that sarcolemmal permeability was associated with muscle length change, but it only accounted for a minimal fraction (21%) of the total strength loss (70%). The magnitude of length change also significantly influenced the degree to which NAC and small molecule calcium modulators protected against ECC-induced strength loss. Conclusions: These results indicate that ECC-induced strength loss of mdx skeletal muscle is dependent on the mechanical properties of the contraction and that mdx muscle is insensitive to ECC at submaximal stimulation frequencies. Rigorous design of ECC protocols is critical for effective use of strength loss as a readout in evaluating potential therapeutics for muscular dystrophy.

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Section: Sarcolemmal Damage Is Associated With the Muscle Length Chansupporting

confidence: 88%

Mechanical factors tune the sensitivity of mdx muscle to eccentric strength loss and its protection by antioxidant and calcium modulators

et al. 2020

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“…While the ROS-based perturbations tested here by us and reported by others previously 27 , 47 , 55 , 60 all demonstrated significant protection of mdx muscle from ECC force loss, the measured protection is incomplete. Other studies have implicated elevated cytosolic calcium 61 – 64 , loss of neuromuscular junction or sarcolemmal membrane excitability 19 , 20 , neuronal nitric oxide synthase 25 , and Akt/PKB signaling 24 in mdx ECC force loss and our results are neither incompatible with nor mutually exclusive of such mechanisms.…”

Section: Discussioncontrasting

confidence: 54%

Loss of peroxiredoxin-2 exacerbates eccentric contraction-induced force loss in dystrophin-deficient muscle

et al. 2018

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Force loss in skeletal muscle exposed to eccentric contraction is often attributed to injury. We show that EDL muscles from dystrophin-deficient mdx mice recover 65% of lost force within 120 min of eccentric contraction and exhibit minimal force loss when the interval between contractions is increased from 3 to 30 min. A proteomic screen of mdx muscle identified an 80% reduction in the antioxidant peroxiredoxin-2, likely due to proteolytic degradation following hyperoxidation by NADPH Oxidase 2. Eccentric contraction-induced force loss in mdx muscle was exacerbated by peroxiredoxin-2 ablation, and improved by peroxiredoxin-2 overexpression or myoglobin knockout. Finally, overexpression of γcyto- or βcyto-actin protects mdx muscle from eccentric contraction-induced force loss by blocking NADPH Oxidase 2 through a mechanism dependent on cysteine 272 unique to cytoplasmic actins. Our data suggest that eccentric contraction-induced force loss may function as an adaptive circuit breaker that protects mdx muscle from injurious contractions.

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“…Furthermore, the exogenous administration of 7,8-dihydroneopterin showed protection comparable to other antioxidants, such as N-acetylcysteine (Whitehead et al, 2008). Other investigations have attenuated eccentric contraction-induced force loss with genetic manipulation of NADPH subunits (Loehr et al, 2016) or by supplementation with green tea extract (Buetler et al, 2002), whereas here we show that 7,8-dihydroneopterin can protect skeletal muscle from force loss in the presence of common pro-oxidants, which are abundant in dystrophic muscle (Disatnik et al, 1998).…”

Section: Eccentric Contractions Facilitate 78-dihydroneopterin Absorsupporting

confidence: 63%

“…Furthermore, the exogenous administration of 7,8‐dihydroneopterin showed protection comparable to other antioxidants, such as N ‐acetylcysteine (Whitehead et al., ). Other investigations have attenuated eccentric contraction‐induced force loss with genetic manipulation of NADPH subunits (Loehr et al., ) or by supplementation with green tea extract (Buetler et al., ), whereas here we show that 7,8‐dihydroneopterin can protect skeletal muscle from force loss in the presence of common pro‐oxidants, which are abundant in dystrophic muscle (Disatnik et al., ). Thus, elevated 7,8‐dihydroneopterin in DMD patients may describe macrophage activation, but it may also provide a muscle‐specific protective mechanism against eccentric‐induced muscle force loss and, consequently, loss of muscle function.…”

Section: Discussioncontrasting

confidence: 52%

Neopterin/7,8‐dihydroneopterin is elevated in Duchenne muscular dystrophy patients and protects mdx skeletal muscle function

Lindsay

Schmiechen

Chamberlain

et al. 2018

Experimental Physiology

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Macrophage infiltration is a hallmark of dystrophin-deficient muscle. We tested the hypothesis that Duchenne muscular dystrophy (DMD) patients would have elevated levels of the macrophage-synthesized pterins, neopterin and 7,8-dihydroneopterin, compared with unaffected age-matched control subjects. Urinary neopterin/creatinine and 7,8-dihydroneopterin/creatinine were elevated in DMD patients, and 7,8-dihydroneopterin/creatinine was associated with patient age and ambulation. Urinary 7,8-dihydroneopterin corrected for specific gravity was also elevated in DMD patients. Given that 7,8-dihydroneopterin is an antioxidant, we then identified a potential role for 7,8-dihydroneopterin in disease pathology. We assessed whether 7,8-dihydroneopterin could: (i) protect against isometric force loss in wild-type skeletal muscle exposed to various pro-oxidants; and (ii) protect wild-type and mdx muscle from eccentric contraction-induced force loss, which has an oxidative component. Force loss was elicited in isolated extensor digitorum longus (EDL) muscles by 10 eccentric contractions, and recovery of force after the contractions was measured in the presence of exogenous 7,8-dihydroneopterin. 7,8-Dihydroneopterin attenuated isometric force loss by wild-type EDL muscles when challenged by H O and HOCl, but exacerbated force loss when challenged by SIN-1 (NO , O , ONOO ). 7,8-Dihydroneopterin attenuated eccentric contraction-induced force loss in mdx muscle. Isometric force production by EDL muscles of mdx mice also recovered to a greater degree after eccentric contractions in the presence of 7,8-dihydroneopterin. The results corroborate macrophage activation in DMD patients, provide a potential protective role for 7,8-dihydroneopterin in the susceptibility of dystrophic muscle to eccentric contractions and indicate that oxidative stress contributes to eccentric contraction-induced force loss in mdx skeletal muscle.

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Eliminating Nox2 reactive oxygen species production protects dystrophic skeletal muscle from pathological calcium influx assessed in vivo by manganese‐enhanced magnetic resonance imaging

Cited by 19 publications

References 61 publications

Mechanical factors tune the sensitivity of mdx muscle to eccentric strength loss and its protection by antioxidant and calcium modulators

Mechanical factors tune the sensitivity of mdx muscle to eccentric strength loss and its protection by antioxidant and calcium modulators

Loss of peroxiredoxin-2 exacerbates eccentric contraction-induced force loss in dystrophin-deficient muscle

Neopterin/7,8‐dihydroneopterin is elevated in Duchenne muscular dystrophy patients and protects mdx skeletal muscle function

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