Is oxidative stress a cause or consequence of disuse muscle atrophy in mice? A proteomic approach in hindlimb‐unloaded mice

Brocca, Lorenza; Pellegrino, Maria Antonietta; Desaphy, Jean-François; Pierno, Sabata; Camerino, Diana Conte; Bottinelli, Roberto

doi:10.1113/expphysiol.2009.050245

Cited by 77 publications

(147 citation statements)

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“…We further postulated that attenuation of oxidative stress would mitigate translocation of nNOS from the sarcolemmal region and significantly ameliorate two predominant phenotypic changes that begin early in mechanical unloading: 1) muscle fiber atrophy and 2) fibertype shift from slow to fast. Previous antioxidant supplementation studies using nonspecific scavengers have yielded inconsistent findings in reducing morphological responses to unloading (3,6,20). In contrast, transfection of the antioxidant enzyme catalase yielded significant protection against atrophy (9).…”

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confidence: 90%

EUK-134 ameliorates nNOSμ translocation and skeletal muscle fiber atrophy during short-term mechanical unloading

Lawler

Kunst

Hord

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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. EUK-134 ameliorates nNOS translocation and skeletal muscle fiber atrophy during short-term mechanical unloading. Am J Physiol Regul Integr Comp Physiol 306: R470-R482, 2014. First published January 29, 2014 doi:10.1152/ajpregu.00371.2013.-Reduced mechanical loading during bedrest, spaceflight, and casting, causes rapid morphological changes in skeletal muscle: fiber atrophy and reduction of slow-twitch fibers. An emerging signaling event in response to unloading is the translocation of neuronal nitric oxide synthase (nNOS) from the sarcolemma to the cytosol. We used EUK-134, a cellpermeable mimetic of superoxide dismutase and catalase, to test the role of redox signaling in nNOS translocation and muscle fiber atrophy as a result of short-term (54 h) hindlimb unloading. Fischer-344 rats were divided into ambulatory control, hindlimb-unloaded (HU), and hindlimb-unloaded ϩ EUK-134 (HU-EUK) groups. EUK-134 mitigated the unloading-induced phenotype, including muscle fiber atrophy and muscle fiber-type shift from slow to fast. nNOS immunolocalization at the sarcolemma of the soleus was reduced with HU, while nNOS protein content in the cytosol increased with unloading. Translocation of nNOS from the sarcolemma to cytosol was virtually abolished by EUK-134. EUK-134 also mitigated dephosphorylation at Thr-32 of FoxO3a during HU. Hindlimb unloading elevated oxidative stress (4-hydroxynonenal) and increased sarcolemmal localization of Nox2 subunits gp91phox (Nox2) and p47phox, effects normalized by EUK-134. Thus, our findings are consistent with the hypothesis that oxidative stress triggers nNOS translocation from the sarcolemma and FoxO3a dephosphorylation as an early event during mechanical unloading. Thus, redox signaling may serve as a biological switch for nNOS to initiate morphological changes in skeletal muscle fibers. atrophy; disuse; skeletal muscle; nNOS; oxidative stress; FoxO3a SKELETAL MUSCLE IS A HIGHLY specialized and adaptable mesodermic tissue capable of rapid remodeling in response to changes in mechanical loading and stretch (28, 38). Transmittance and detection of loading in skeletal muscle are paramount in regulating differentiation, cell growth, and protein turnover. The ability to sense and relay loading (i.e., mechanotransduction) is, in part, performed by proteins adjacent to and spanning cell membranes (i.e., sarcolemma) in skeletal muscle (47). Mechanical unloading that occurs with limb casting, splinting, bed rest, and spaceflight, elicits a substantial loss of forcegenerating capacity, linked to a diminishment in muscle fiber cross-sectional area or atrophy (12, 23). The unloading phenotype also includes a shift of a portion of skeletal muscle fibers from slow-twitch to fast-twitch (12). Muscle atrophy that occurs with unloading is coupled to a net loss of contractile proteins, a function of increased protein degradation combined with a decrease in protein synthesis (12,23). Recent studies emphasize the importance of proteolytic pathways, including ubiquitin proteasome, calpains, autophagy...

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confidence: 90%

EUK-134 ameliorates nNOSμ translocation and skeletal muscle fiber atrophy during short-term mechanical unloading

Lawler

Kunst

Hord

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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“…A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 5 However, this approach has been demonstrated widely useful in a number of recent works [27][28][29][30].…”

Section: Page 5 Of 47mentioning

confidence: 99%

“…The downregulation of glycolytic enzymes is a symptom of energy production failure, and can contribute to muscle damage. Interestingly a general impairment of energy metabolism have been observed in conditions of muscle atrophy [29], which may develop also during statin myopathy [50]. Moreover, it has been shown that hereditary muscle glycogenoses in humans are characterized by defective glycolytic enzymes, including beta enolase, and leads to different degree of myopathy, ranging from cramps to myoglobinuria [51][52].…”

Section: Glycolytic Metabolismmentioning

confidence: 99%

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Statin or fibrate chronic treatment modifies the proteomic profile of rat skeletal muscle

Camerino

Pellegrino

Brocca

et al. 2011

Biochemical Pharmacology

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Statins and fibrates can cause myopathy. To further understand the causes of the damage we performed a proteome analysis in fast-twitch skeletal muscle of rats chronically treated with different hypolipidemic drugs. The proteomic maps were obtained from extensor digitorum longus (EDL) muscles of rats treated for 2-months with 10mg/kg atorvastatin, 20mg/kg fluvastatin, 60mg/kg fenofibrate and control rats. The proteins differentially expressed were identified by mass spectrometry and further analysed by immunoblot analysis. We found a significant modification in 40 out of 417 total spots analysed in atorvastatin treated rats, 15 out of 436 total spots in fluvastatin treated rats and 21 out of 439 total spots in fenofibrate treated rats in comparison to controls. All treatments induced a general tendency to a down-regulation of protein expression; in particular, atorvastatin affected the protein pattern more extensively with respect to the other treatments.Energy production systems, both oxidative and glycolytic enzymes and creatine kinase, were downregulated following atorvastatin administration, whereas fenofibrate determined mostly alterations in glycolytic enzymes and creatine kinase, oxidative enzymes being relatively spared. Additionally, all treatments resulted in some modifications of proteins involved in cellular defenses against oxidative stress, such as heat shock proteins, and of myofibrillar proteins. These results were confirmed by immunoblot analysis. In conclusions, the proteomic analysis showed that either statin or fibrate administration can modify the expression of proteins essential for skeletal muscle function suggesting potential mechanisms for statin myopathy.

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“…This is consistent with other studies reporting that administration of vitamin E (a small molecule antioxidant) results in decreased lipid peroxidation in skeletal muscle (Kondo et al, 1991;Servais et al, 2007). The reduced iliofibularis lipid peroxidation in aestivation when TAC is also reduced, and no reduction of gastrocnemius lipid peroxidation in aestivation when TAC is reduced at 24°C or increased at 30°C, suggests a different suite of in vivo conditions between the two muscles, such as muscle-specific regulation of other antioxidants, mitochondrial properties, degree of coupling of ROS formation to oxygen consumption and differences in the signalling requirements and metabolic program changes of the muscles (Anderson and Neufer, 2006;Brocca et al, 2010).…”

Section: Oxidative Damage Lipid Peroxidationmentioning

confidence: 99%

Each to their own: skeletal muscles of different function use different biochemical strategies during aestivation at high temperature

Young

Cramp

Franklin

2012

Journal of Experimental Biology

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SUMMARYPreservation of muscle morphology depends on a continuing regulatory balance between molecules that protect and molecules that damage muscle structural integrity. Excessive disruption of the biochemical balance that favours reactive oxygen species (ROS) in disused muscles may lead to oxidative stress, which in turn is associated with increased atrophic or apoptotic signalling and/or oxidative damage to the muscle and thus muscle disuse atrophy. Increases in the rate of oxygen consumption likely increase the overall generation of ROS in vivo. Temperature-induced increases in oxygen consumption rate occur in some muscles of ectotherms undergoing prolonged muscular disuse during aestivation. In the green-striped burrowing frog, Cyclorana alboguttata, both large jumping and small non-jumping muscles undergo atrophy seemingly commensurate with their rate of oxygen consumption during aestivation. However, because the extent of atrophy in these muscles is not enhanced at higher temperatures, despite a temperature-sensitive rate of oxygen consumption in the jumping muscle, we proposed that muscles are protected by biochemical means that, when mobilised at higher temperatures, inhibit atrophy. We proposed that the biochemical response to temperature would be muscle-specific. We examined the effect of temperature on the antioxidant and heat shock protein systems and determined the extent of oxidative damage to lipids and proteins in two functionally different skeletal muscles, the gastrocnemius (jumping muscle) and the iliofibularis (non-jumping muscle), by aestivating frogs at 24 and 30°C for 6months. We assayed small molecule antioxidant capacity, mitochondrial and cytosolic superoxide dismutase activities and Hsp70 concentrations to show that protective mechanisms in disused muscles are differentially regulated with respect to both temperature and aestivation. High aestivation temperature results in an antioxidant response in the metabolically temperaturesensitive jumping muscle. We assayed lipid peroxidation and protein oxidation to show that oxidative damage is apparent during aestivation and its pattern is muscle-specific, but unaffected by temperature. Consideration is given to how the complex responses of muscle biochemistry inform the different strategies muscles may use in regulating their oxidative environment during extended disuse and disuse at high temperature.

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Is oxidative stress a cause or consequence of disuse muscle atrophy in mice? A proteomic approach in hindlimb‐unloaded mice

Cited by 77 publications

References 75 publications

EUK-134 ameliorates nNOSμ translocation and skeletal muscle fiber atrophy during short-term mechanical unloading

EUK-134 ameliorates nNOSμ translocation and skeletal muscle fiber atrophy during short-term mechanical unloading

Statin or fibrate chronic treatment modifies the proteomic profile of rat skeletal muscle

Each to their own: skeletal muscles of different function use different biochemical strategies during aestivation at high temperature

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