Lipid hydroperoxides in sarcopenia and muscle wasting: mechanisms and intervention
脂质氢过氧化物在肌肉减少症和肌肉萎缩中的作用:机制和干预
基本信息
- 批准号:10634499
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-01-01 至 2026-12-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAgeAge MonthsAge YearsAgingAnimal GeneticsAnimal ModelArachidonate 15-LipoxygenaseArachidonic AcidsAtrophicAttenuatedBody CompositionCessation of lifeCommunicationCytoplasmDataDenervationDevelopmentDiabetes MellitusEicosanoidsElectron TransportEnzymesFiberFractureFunctional disorderGenerationsGeneticGenetic InductionGoalsHand StrengthHealthHealth ExpendituresHindlimbHydrogen PeroxideInterventionKnockout MiceLipid PeroxidationLipid PeroxidesLipidsMaintenanceMalnutritionMeasuresMediatorMembraneMental DepressionMentorsMitochondriaModelingMorphologyMotor NeuronsMovementMusMuscleMuscle FibersMuscle ProteinsMuscle functionMuscular AtrophyNeuromuscular JunctionOxidative StressPatientsPermeabilityPhospholipase A2PhospholipidsPopulationPrevalenceProductionProtein BiosynthesisProteinsPsyche structureQuality of lifeResearch TechnicsRiskRunningScientistSecondary toSkeletal MuscleStructureSuperoxidesSyndromeTestingTrainingVeteransadverse outcomeage relatedage-related muscle lossagedcatalasedesigneffective interventioneffective therapyexperimental studyfallsgene therapyglutathione peroxidasehealthspanimprovedmeetingsmitochondrial dysfunctionmouse modelmuscle agingmuscle degenerationmuscle formmuscle strengthnerve supplynoveloverexpressionoxidationpharmacologicphysically handicappedprotein biomarkersprotein degradationreduced muscle massresponsesarcopeniaskeletal muscle wastingstable isotopesymposiumtherapeutic targettherapy design
项目摘要
SIGNIFICANCE TO VETERANS HEALTH: Two-thirds of all veterans are 55 years of age or older. Sarcopenia
is a syndrome that effects approximately 25% of the U.S. population over the age of 70 characterized by
progressive loss of skeletal muscle mass and strength with an increased risk of adverse outcomes such as
physical disability, poor quality of life and even death. Further, the development of sarcopenia may lead to
secondary health conditions such as disuse, malnutrition, falls, fractures and diabetes. In addition to the physical
ailments that accompany patients that suffer from sarcopenia, sarcopenia contributes to over $18.5 billion dollars
of total health care expenditures. The prevalence of sarcopenia is higher in subjects presenting another health
condition than in healthy subjects including mental conditions such as depression that are common among
veterans. There are currently no effective treatments for sarcopenia because underlying mechanisms are not
fully elucidated. OBJECTIVES: The objective of this study is to test if denervation induced generation of lipid
hydroperoxides (LOOHs), through the enzyme 12/15-Lipoxygenase (12/15-Lox) or through direct oxidation of
lipids, leads to neuromuscular junction (NMJ) disruption and mitochondrial dysfunction that initiates muscle
atrophy, muscle protein breakdown, and weakness. RESEARCH PLAN: In Specific Aim 1, I will test the effect
of reducing LOOHs via treatment with the LOOH scavenger liproxstatin-1 on mitochondrial function, NMJ
structure and function, protein turnover, and maintenance of muscle mass and function in aged mice. In Specific
Aim 2, I will test the effect of muscle specific genetic deletion of 12/15-Lox, an enzyme that generates eicosanoids
and oxylipins, on the maintenance of muscle mass and function in aged mice. Finally, in Specific Aim 3, I will
test the effect of muscle specific overexpression of glutathione peroxidase 4 (GPx4), an enzyme that reduces
LOOHs within membranes, on the maintenance of muscle mass and function in aged mice. We will use a
combination of pharmacological approaches, genetic mouse models, and novel research techniques to test the
central hypothesis. ANTICIPATED OUTCOMES: All of my Specific Aims focus on reducing skeletal muscle
LOOHs (either enzymatically generated or direct oxidation of lipids) in response to age-related denervation. I
hypothesize that my interventions will ameliorate skeletal muscle atrophy and dysfunction in hindlimb muscle
from aged mice by reducing lipid peroxidation, improving mitochondrial function, reducing rates of protein
degradation, and maintaining NMJ integrity. My preliminary data clearly shows that LOOH generation is elevated
in aged muscle, and that LOOH generation is strongly correlated to muscle mass loss in models of denervation
atrophy. For skeletal muscle mass loss to occur, rates of protein degradation have to be greater than rates of
protein synthesis. Therefore, my interventions have to reduce rates of protein degradation and/or increase rates
of protein synthesis in denervated muscle. There are multiple lines of evidence that shows mitochondrial health
is important for the maintenance of skeletal muscle mass and function. My preliminary data shows that
overexpression of GPx4 in a model of accelerated sarcopenia improves mitochondrial function, which may
reduce muscle mass loss. Therefore, we hypothesize that reducing LOOHs in muscle will improve mitochondrial
function in aged mice. Finally, denervation can propagate oxidative stress and NMJ disruption in surrounding
fibers. We predict that reducing LOOHs in muscle will slow NMJ degradation of the surrounding fibers.
TRAINING PLAN: My short-term goals are to delineate the mechanisms of LOOH driven sarcopenia and receive
training in oxidative stress, aging, the use of stable isotopes, using genetic animal models, and scientific
communication. I will receive this training through a combination of meetings with my mentoring team,
conferences, presentation, formal courses, and performing experiments. The training plan I have outlined will
allow me to achieve my long-term goal of becoming an independent VA scientist.
SIGNIFICANCE TO VETERANS HEALTH: Two-thirds of all veterans are 55 years of age or older. Sarcopenia
is a syndrome that effects approximately 25% of the U.S. population over the age of 70 characterized by
progressive loss of skeletal muscle mass and strength with an increased risk of adverse outcomes such as
physical disability, poor quality of life and even death. Further, the development of sarcopenia may lead to
secondary health conditions such as disuse, malnutrition, falls, fractures and diabetes. In addition to the physical
ailments that accompany patients that suffer from sarcopenia, sarcopenia contributes to over $18.5 billion dollars
of total health care expenditures. The prevalence of sarcopenia is higher in subjects presenting another health
condition than in healthy subjects including mental conditions such as depression that are common among
veterans. There are currently no effective treatments for sarcopenia because underlying mechanisms are not
fully elucidated. OBJECTIVES: The objective of this study is to test if denervation induced generation of lipid
hydroperoxides (LOOHs), through the enzyme 12/15-Lipoxygenase (12/15-Lox) or through direct oxidation of
lipids, leads to neuromuscular junction (NMJ) disruption and mitochondrial dysfunction that initiates muscle
atrophy, muscle protein breakdown, and weakness. RESEARCH PLAN: In Specific Aim 1, I will test the effect
of reducing LOOHs via treatment with the LOOH scavenger liproxstatin-1 on mitochondrial function, NMJ
structure and function, protein turnover, and maintenance of muscle mass and function in aged mice. In Specific
Aim 2, I will test the effect of muscle specific genetic deletion of 12/15-Lox, an enzyme that generates eicosanoids
and oxylipins, on the maintenance of muscle mass and function in aged mice. Finally, in Specific Aim 3, I will
test the effect of muscle specific overexpression of glutathione peroxidase 4 (GPx4), an enzyme that reduces
LOOHs within membranes, on the maintenance of muscle mass and function in aged mice. We will use a
combination of pharmacological approaches, genetic mouse models, and novel research techniques to test the
central hypothesis. ANTICIPATED OUTCOMES: All of my Specific Aims focus on reducing skeletal muscle
LOOHs (either enzymatically generated or direct oxidation of lipids) in response to age-related denervation. I
hypothesize that my interventions will ameliorate skeletal muscle atrophy and dysfunction in hindlimb muscle
from aged mice by reducing lipid peroxidation, improving mitochondrial function, reducing rates of protein
degradation, and maintaining NMJ integrity. My preliminary data clearly shows that LOOH generation is elevated
in aged muscle, and that LOOH generation is strongly correlated to muscle mass loss in models of denervation
atrophy. For skeletal muscle mass loss to occur, rates of protein degradation have to be greater than rates of
protein synthesis. Therefore, my interventions have to reduce rates of protein degradation and/or increase rates
of protein synthesis in denervated muscle. There are multiple lines of evidence that shows mitochondrial health
is important for the maintenance of skeletal muscle mass and function. My preliminary data shows that
overexpression of GPx4 in a model of accelerated sarcopenia improves mitochondrial function, which may
reduce muscle mass loss. Therefore, we hypothesize that reducing LOOHs in muscle will improve mitochondrial
function in aged mice. Finally, denervation can propagate oxidative stress and NMJ disruption in surrounding
fibers. We predict that reducing LOOHs in muscle will slow NMJ degradation of the surrounding fibers.
TRAINING PLAN: My short-term goals are to delineate the mechanisms of LOOH driven sarcopenia and receive
training in oxidative stress, aging, the use of stable isotopes, using genetic animal models, and scientific
communication. I will receive this training through a combination of meetings with my mentoring team,
conferences, presentation, formal courses, and performing experiments. The training plan I have outlined will
allow me to achieve my long-term goal of becoming an independent VA scientist.
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Jacob Levi Brown其他文献
Jacob Levi Brown的其他文献
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{{ truncateString('Jacob Levi Brown', 18)}}的其他基金
Lipid hydroperoxides in sarcopenia and muscle wasting: mechanisms and intervention
脂质氢过氧化物在肌肉减少症和肌肉萎缩中的作用:机制和干预
- 批准号:
10366483 - 财政年份:2022
- 资助金额:
-- - 项目类别:
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