Strain-Dependent Variation in Acute Ischemic Muscle Injury

Schmidt, Cameron A.; Amorese, Adam J.; Ryan, Terence E.; Goldberg, Emma J.; Tarpey, Michael D.; Green, Thomas D.; Karnekar, Reema; Yamaguchi, Dean T.; Spangenburg, Espen E.; McClung, Joseph M.

doi:10.1016/j.ajpath.2018.01.008

Cited by 28 publications

(50 citation statements)

References 58 publications

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“…Previous reports have indicated that dystrophin IF staining is rapidly reduced in skeletal and cardiac muscle during early myonecrosis(19,32). Immunofluorescent staining for the sarcolemmal protein dystrophin and the extracellular matrix protein laminin was performed on a subset of transverse sectioned muscles to assess the possibility that muscles were incurring damage during the contraction protocols.…”

Section: Resultsmentioning

confidence: 94%

“…The muscles were then equilibrated for 10 mins, followed by stimulated isokinetic contractions every 10 mins for 180 mins (18 total contractions). We chose this timing based on our previous observation that excitation contraction coupling is impaired in muscles isolated from BALB/c mice 180 minutes after induction of acute hindlimb ischemia (in the absence of histological signs of tissue necrosis)(19). A second force frequency curve was measured following the 180-min.…”

Section: Methodsmentioning

confidence: 99%

“…In a previous study, using an in vivo mouse hindlimb ischemia model (without reperfusion), we found that myonecrosis develops between three and six hours after the onset of ischemia and is accompanied by a complete loss of contractile function(19). This led us to examine the <3-hour time domain in this study to better characterize the exact temporal nature of muscle functional impairments and metabolite changes that occur under ischemic conditions.…”

Section: Introductionmentioning

confidence: 99%

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Effects of fasting induced carbohydrate depletion on murine ischemic skeletal muscle function

Schmidt

Goldberg²,

Green³

et al. 2019

Preprint

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J.M.M.) 20 21 22 2 23 Abstract 24 Stored muscle carbohydrate supply and energetic efficiency constrain muscle functional 25 capacity during exercise and are influenced by common physiological variables (e.g. age,26 diet, and physical activity level). Whether these constraints affect overall functional 27 capacity or the timing of muscle energetic failure during acute ischemia is not known. We 28 interrogated skeletal muscle contractile properties in two anatomically distinct hindlimb 29 muscles that have well characterized differences in energetic efficiency (locomotory-30 extensor digitorum longus (EDL) and postural-soleus muscles) under conditions of 31 reduced carbohydrate supply. 180 mins of acute ischemia resulted in complete energetic 32 failure in all muscles tested, indicated by: loss of force production, substantial reductions 33 in total adenosine nucleotide pool intermediates, and increased adenosine nucleotide 34 degradation product -inosine monophosphate (IMP). These changes occurred in the 35 absence of apparent myofiber structural damage assessed histologically by both 36 transverse section and whole mount. Restriction of the available intracellular carbohydrate 37 pool by fasting (~50% decrease in skeletal muscle) did not significantly alter the timing to 38 muscle functional impairment or affect the overall force/work capacities of either muscle 39 type. Fasting did cause rapid development of passive tension in both muscle types, which 40 may have implications for optimal timing of reperfusion or administration of precision 41 therapeutics. 42 43 44 45 46 47 48 49 Introduction 50 Ischemic skeletal muscle necrosis occurs concurrently with several common clinical 51 conditions (e.g. peripheral arterial disease, compartment syndrome, or diabetic necrosis)52 and is a complicating factor of successful muscle graft transplantation(1-3). The severity 53 of necrosis during an ischemic episode has long been considered a sole function of time, 54 temperature, and magnitude of the hypoxic insult(4,5). However, the timing of the events 55 that precede irreversible functional impairment and necrosis during ischemia may also 56 depend on other key variables including: metabolic rate; contractile efficiency; and the size 57 of the stored carbohydrate pool(4). Carbohydrate metabolism is key, as muscle energy 58 supply becomes dependent on anaerobic fermentation of stored carbohydrate sources 59 during ischemia(6-8). Glycogen is the primary storage form of carbohydrate in skeletal 60 muscle, and its storage/utilization can be influenced by acute environmental factors as 61 well as chronic diseases(9-14). 6263 Previous studies have examined the time dependent changes of metabolites and 64 contractile function in rodent skeletal muscle following ischemia with reperfusion (I/R)(15-65 18). Several important observations can be gleaned from these studies: First, locomotory 66 (fast glycolytic) muscles experienced more damage compared to postural (slow oxidative) 67 muscles(15,17). Second, The degree of initial injury ...

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Section: Resultsmentioning

confidence: 94%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Effects of fasting induced carbohydrate depletion on murine ischemic skeletal muscle function

Schmidt

Goldberg²,

Green³

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…In a previous study, using an in vivo mouse hindlimb ischemia model (without reperfusion), we found that myonecrosis develops between three and six hours after the onset of ischemia and is accompanied by a complete loss of contractile function [19]. This led us to examine the <3-hour time domain in this study to better define the timing of muscle functional impairments and associated terminal metabolite changes that occur during acute hypoxia.…”

Section: Introductionmentioning

confidence: 98%

“…Our data provide a novel characterization of hypoxic muscle mechanical/energetic failure and paint a detailed picture of the timing of these impairments. This information can be used in conjunction with existing in vivo rodent hindlimb ischemia/reperfusion studies [5,16,17,19] to generate new hypotheses regarding optimal timing of reperfusion or administration of precision therapeutics.…”

Section: Introductionmentioning

confidence: 99%

Effects of fasting on isolated murine skeletal muscle contractile function during acute hypoxia

et al. 2020

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Stored muscle carbohydrate supply and energetic efficiency constrain muscle functional capacity during exercise and are influenced by common physiological variables (e.g. age, diet, and physical activity level). Whether these constraints affect overall functional capacity or the timing of muscle energetic failure during acute hypoxia is not known. We interrogated skeletal muscle contractile properties in two anatomically distinct rodent hindlimb muscles that have well characterized differences in energetic efficiency (locomotory-extensor digitorum longus (EDL) and postural-soleus muscles) following a 24 hour fasting period that resulted in substantially reduced muscle carbohydrate supply. 180 mins of acute hypoxia resulted in complete energetic failure in all muscles tested, indicated by: loss of force production, substantial reductions in total adenosine nucleotide pool intermediates, and increased adenosine nucleotide degradation product-inosine monophosphate (IMP). These changes occurred in the absence of apparent myofiber structural damage assessed histologically by both transverse section and whole mount. Fasting and the associated reduction of the available intracellular carbohydrate pool (~50% decrease in skeletal muscle) did not significantly alter the timing to muscle functional impairment or affect the overall force/work capacities of either muscle type. Fasting resulted in greater passive tension development in both muscle types, which may have implications for the design of pre-clinical studies involving optimal timing of reperfusion or administration of precision therapeutics.

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Interventional‐ and amputation‐stage muscle proteomes in the chronically threatened ischemic limb

Ryan

Kim

Scali

et al. 2022

Clinical & Translational Med

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Background Despite improved surgical approaches for chronic limb‐threatening ischemia (CLTI), amputation rates remain high and contributing tissue‐level factors remain unknown. The purpose of this study was twofold: (1) to identify differences between the healthy adult and CLTI limb muscle proteome, and (2) to identify differences in the limb muscle proteome of CLTI patients prior to surgical intervention or at the time of amputation. Methods and results Gastrocnemius muscle was collected from non‐ischemic controls (n = 19) and either pre‐interventional surgery (n = 10) or at amputation outcome (n = 29) CLTI patients. All samples were subjected to isobaric tandem‐mass‐tag‐assisted proteomics. The mitochondrion was the primary classification of downregulated proteins (> 70%) in CLTI limb muscles and paralleled robust functional mitochondrial impairment. Upregulated proteins (> 38%) were largely from the extracellular matrix. Across the two independent sites, 39 proteins were downregulated and 12 upregulated uniformly. Pre‐interventional CLTI muscles revealed a robust upregulation of mitochondrial proteins but modest functional impairments in fatty acid oxidation as compared with controls. Comparison of pre‐intervention and amputation CLTI limb muscles revealed mitochondrial proteome and functional deficits similar to that between amputation and non‐ischemic controls. Interestingly, these observed changes occurred despite 62% of the amputation CLTI patients having undergone a prior surgical intervention. Conclusions The CLTI proteome supports failing mitochondria as a phenotype that is unique to amputation outcomes. The signature of pre‐intervention CLTI muscle reveals stable mitochondrial protein abundance that is insufficient to uniformly prevent functional impairments. Taken together, these findings support the need for future longitudinal investigations aimed to determine whether mitochondrial failure is causally involved in amputation outcomes from CLTI.

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Strain-Dependent Variation in Acute Ischemic Muscle Injury

Cited by 28 publications

References 58 publications

Effects of fasting induced carbohydrate depletion on murine ischemic skeletal muscle function

Effects of fasting induced carbohydrate depletion on murine ischemic skeletal muscle function

Effects of fasting on isolated murine skeletal muscle contractile function during acute hypoxia

Interventional‐ and amputation‐stage muscle proteomes in the chronically threatened ischemic limb

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