Mitochondrial oxidative stress impairs contractile function but paradoxically increases muscle mass via fibre branching

Ahn, Bumsoo; Ranjit, Rojina; Premkumar, Pavithra; Pharaoh, Gavin; Piekarz, Katarzyna M.; Matsuzaki, Satoshi; Claflin, Dennis R.; Riddle, Kaitlyn; Judge, Jennifer; Bhaskaran, Shylesh; Natarajan, Kavithalakshmi Satara; Barboza, Erika; Wronowski, Benjamin; Kinter, Michael; Humphries, Kenneth M.; Griffin, Timothy M.; Freeman, Willard M.; Richardson, Arlan; Brooks, Susan V.; Remmen, Holly Van

doi:10.1002/jcsm.12375

Cited by 59 publications

(58 citation statements)

References 67 publications

(182 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Damaged proteins induce an increase in activation of protein breakdown signalling, promoting muscle loss. 10,11 Tissues possess scavenging antioxidant enzymes that act to neutralize radicals and prevent oxidative stress-mediated tissue dysfunction. 12 However, scavenging enzymes are dysregulated in many disease conditions, 13,14 leading to oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

Cancer cachexia in a mouse model of oxidative stress

Brown

Lawrence

Ahn

et al. 2020

J cachexia sarcopenia muscle

Self Cite

View full text Add to dashboard Cite

Background Cancer is associated with muscle atrophy (cancer cachexia) that is linked to up to 40% of cancer-related deaths. Oxidative stress is a critical player in the induction and progression of age-related loss of muscle mass and weakness (sarcopenia); however, the role of oxidative stress in cancer cachexia has not been defined. The purpose of this study was to examine if elevated oxidative stress exacerbates cancer cachexia. Methods Cu/Zn superoxide dismutase knockout (Sod1KO) mice were used as an established mouse model of elevated oxidative stress. Cancer cachexia was induced by injection of one million Lewis lung carcinoma (LLC) cells or phosphate-buffered saline (saline) into the hind flank of female wild-type mice or Sod1KO mice at approximately 4 months of age. The tumour developed for 3 weeks. Muscle mass, contractile function, neuromuscular junction (NMJ) fragmentation, metabolic proteins, mitochondrial function, and motor neuron function were measured in wild-type and Sod1KO saline and tumour-bearing mice. Data were analysed by two-way ANOVA with Tukey-Kramer post hoc test when significant F ratios were determined and α was set at 0.05. Unless otherwise noted, results in abstract are mean ±SEM. Results Muscle mass and cross-sectional area were significantly reduced, in tumour-bearing mice. Metabolic enzymes were dysregulated in Sod1KO mice and cancer exacerbated this phenotype. NMJ fragmentation was exacerbated in tumour-bearing Sod1KO mice. Myofibrillar protein degradation increased in tumour-bearing wild-type mice (wild-type saline, 0.00847 ± 0.00205; wildtype LLC, 0.0211 ± 0.00184) and tumour-bearing Sod1KO mice (Sod1KO saline, 0.0180 ± 0.00118; Sod1KO LLC, 0.0490 ± 0.00132). Muscle mitochondrial oxygen consumption was reduced in tumour-bearing mice compared with saline-injected wild-type mice. Mitochondrial protein degradation increased in tumour-bearing wild-type mice (wild-type saline, 0.0204 ± 0.00159; wild-type LLC, 0.167 ± 0.00157) and tumour-bearing Sod1KO mice (Sod1KO saline, 0.0231 ± 0.00108; Sod1 KO LLC, 0.0645 ± 0.000631). Sciatic nerve conduction velocity was decreased in tumour-bearing wild-type mice (wild-type saline, 38.2 ± 0.861; wild-type LLC, 28.8 ± 0.772). Three out of eleven of the tumour-bearing Sod1KO mice did not survive the 3-week period following tumour implantation. Conclusions Oxidative stress does not exacerbate cancer-induced muscle loss; however, cancer cachexia may accelerate NMJ disruption.

show abstract

Section: Introductionmentioning

confidence: 99%

Cancer cachexia in a mouse model of oxidative stress

Brown

Lawrence

Ahn

et al. 2020

J cachexia sarcopenia muscle

Self Cite

View full text Add to dashboard Cite

show abstract

“…Because this ROS potentiation in type II fibers is coupled with decreased ability to combat lipid stress in comparison to type I fibers, cellular homeostasis is disrupted predisposing the proteins and other cellular components to damage and dysfunction. In fact, compromised cellular redox homeostasis is suggested for impairments in NMJ integrity and function (Sakellariou et al 2017) (Ahn et al 2019) and likely contributes in the observed accelerated alterations in the NMJs of type II fibers with aging (Prakash and Sieck 1998).…”

mentioning

confidence: 99%

Lipotoxicity, aging, and muscle contractility: does fiber type matter?

2019

View full text Add to dashboard Cite

Sarcopenia is a universal characteristic of the aging process and is often accompanied by increases in whole-body adiposity. These changes in body composition have important clinical implications, given that loss of muscle and gain of fat mass are both significantly and independently associated with declining physical performance as well as an increased risk for disability, hospitalizations, and mortality in older individuals. This increased fat mass is not exclusively stored in adipose depots but may become deposited in non-adipose tissues, such as skeletal muscle, when the oxidative capacity of the adipose tissue itself is exceeded. The redistributed adipose tissue is thought to exert detrimental local effects on the muscle environment given the close proximity. Thus, sarcopenia observed with aging may be better defined in the context of loss of muscle quality rather than loss of muscle quantity per se. In this perspective, we briefly review the age-related physiological changes in cellularity, secretory profiles, and inflammatory status of adipose tissue which drive lipotoxicity (spillover) of skeletal muscle and then provide evidence of how this may affect specific fiber type contractility. We focus on biological contributors (cellular machinery) to contractility for which there is some evidence of vulnerability to lipid stress distinguishing between fiber types.

show abstract

“…While muscle respiration depends on electrons entering the electron transport chain from both complexes I and II, fat mitochondria depend primarily on complex II-linked respiration. ETC complex II is highly sensitive to oxidative damage, which could partially explain the age-related decrease in OXPHOS capacity [92]. Basal hydroperoxide production was approximately 4.5 times higher in fat biopsies than in muscle.…”

Section: Discussionmentioning

confidence: 97%

Disparate Central and Peripheral Effects of Circulating IGF-1 Deficiency on Tissue Mitochondrial Function

et al. 2019

Self Cite

View full text Add to dashboard Cite

Age-related decline in circulating levels of insulin-like growth factor (IGF)-1 is associated with reduced cognitive function, neuronal aging, and neurodegeneration. Decreased mitochondrial function along with increased reactive oxygen species (ROS) and accumulation of damaged macromolecules are hallmarks of cellular aging. Based on numerous studies indicating pleiotropic effects of IGF-1 during aging, we compared the central and peripheral effects of circulating IGF-1 deficiency on tissue mitochondrial function using an inducible liver IGF-1 knockout (LID). Circulating levels of IGF-1 (~75%) were depleted in adult male Igf1 f/f mice via AAV-mediated knockdown of hepatic IGF-1 at 5 months of age. Cognitive function was evaluated at 18 months using the radial arm water maze and glucose and insulin tolerance assessed. Mitochondrial function was analyzed in hippocampus, muscle, and visceral fat tissues using high-resolution respirometry O2K as well as redox status and oxidative stress in the cortex. Peripherally, IGF-1 deficiency did not significantly impact muscle mass or mitochondrial function. Aged LID mice were insulin resistant and exhibited~60% less adipose tissue but increased fat mitochondrial respiration (20%). The effects on fat metabolism were attributed to increases in growth hormone. Centrally, IGF-1 deficiency impaired hippocampal-dependent spatial acquisition as well as reversal learning in male mice. Hippocampal mitochondrial OXPHOS coupling efficiency and cortex ATP levels (~50%) were decreased and hippocampal oxidative stress (protein carbonylation and F 2-isoprostanes) was increased. These data suggest that IGF-1 is critical for regulating mitochondrial function, redox status, and spatial learning in the central nervous system but has limited impact on peripheral (liver and muscle) metabolism with age. Therefore, IGF-1 deficiency with age may increase sensitivity to damage in the brain and propensity for cognitive deficits. Targeting mitochondrial function in the brain may be an avenue for therapy of age-related impairment of cognitive function. Regulation of mitochondrial function and redox status by IGF-1 is essential to maintain brain function and coordinate hippocampal-dependent spatial learning. While a decline in IGF-1 in the periphery may be beneficial to avert cancer progression, diminished central IGF-1 signaling may mediate, in part, age-related cognitive dysfunction and cognitive pathologies potentially by decreasing mitochondrial function. Highlights Circulating IGF-1 deficiency: • Has pleiotropic effects on central and peripheral tissues. • Induces impairments in hippocampal learning and memory. • Decreases hippocampal mitochondrial oxygen coupling efficiency. • Increases stress response and oxidative damage in brain.

show abstract

Mitochondrial oxidative stress impairs contractile function but paradoxically increases muscle mass via fibre branching

Cited by 59 publications

References 67 publications

Cancer cachexia in a mouse model of oxidative stress

Cancer cachexia in a mouse model of oxidative stress

Lipotoxicity, aging, and muscle contractility: does fiber type matter?

Disparate Central and Peripheral Effects of Circulating IGF-1 Deficiency on Tissue Mitochondrial Function

Contact Info

Product

Resources

About