scholarly journals Skeletal muscle mitochondrial respiration in a model of age-related osteoarthritis is impaired after dietary rapamycin

2021 ◽  
Author(s):  
Christian J Elliehausen ◽  
Dennis M Minton ◽  
Alexander D Nichol ◽  
Adam R Konopka
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
Guinea Pigs ◽  
Muscle Size ◽  
Skeletal Muscle Mitochondria ◽  
Age Related ◽  
End Stage ◽  
And Function ◽  
Permeabilized Muscle

A decline in skeletal muscle mitochondrial function is associated with the loss of skeletal muscle size and function during knee osteoarthritis (OA). We have recently reported that the 12-weeks of dietary rapamycin (Rap, 14ppm), with or without metformin (Met, 1000ppm), increased plasma glucose and OA severity in male Dunkin Hartley (DH) guinea pigs, a model of naturally occurring, age-related OA. The purpose of the current study was to determine if increased OA severity after dietary Rap and Rap+Met was accompanied by impaired skeletal muscle mitochondrial function. Mitochondrial respiration and hydrogen peroxide (H2O2) emissions were evaluated in permeabilized muscle fibers via high-resolution respirometry and fluorometry using either a saturating bolus or titration of ADP. Rap and Rap+Met decreased complex I (CI)-linked respiration and increased ADP sensitivity, consistent with previous findings in patients with end-stage OA. Rap also tended to decrease mitochondrial H2O2 emissions, however, this was no longer apparent after normalizing to respiration. The decrease in CI-linked respiration was accompanied with lower CI protein abundance. This is the first inquiry into how lifespan extending treatments Rap and Rap+Met can influence skeletal muscle mitochondria in a model of age-related OA. Collectively, our data suggest that Rap with or without Met inhibits CI-linked capacity and increases ADP sensitivity in DH guinea pigs that have greater OA severity.

Maintenance of Skeletal Muscle Mitochondria in Health, Exercise, and Aging

2019 ◽  
Vol 81 (1) ◽  
pp. 19-41 ◽  
Author(s):  
David A. Hood ◽  
Jonathan M. Memme ◽  
Ashley N. Oliveira ◽  
Matthew Triolo
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Mitochondrial Function ◽  
High Functioning ◽  
Muscle Disuse ◽  
Skeletal Muscle Mitochondria ◽  
Single Bout ◽  
Atp Supply ◽  
And Function ◽  
Exercise And Aging

Mitochondria are critical organelles responsible for regulating the metabolic status of skeletal muscle. These organelles exhibit remarkable plasticity by adapting their volume, structure, and function in response to chronic exercise, disuse, aging, and disease. A single bout of exercise initiates signaling to provoke increases in mitochondrial biogenesis, balanced by the onset of organelle turnover carried out by the mitophagy pathway. This accelerated turnover ensures the presence of a high functioning network of mitochondria designed for optimal ATP supply, with the consequence of favoring lipid metabolism, maintaining muscle mass, and reducing apoptotic susceptibility over the longer term. Conversely, aging and disuse are associated with reductions in muscle mass that are in part attributable to dysregulation of the mitochondrial network and impaired mitochondrial function. Therefore, exercise represents a viable, nonpharmaceutical therapy with the potential to reverse and enhance the impaired mitochondrial function observed with aging and chronic muscle disuse.

scholarly journals Subpopulation-specific differences in skeletal muscle mitochondria in humans with obesity: insights from studies employing acute nutritional and exercise stimuli

2020 ◽  
Vol 318 (4) ◽  
pp. E538-E553
Author(s):  
Nisreen Wahwah ◽  
Katon A. Kras ◽  
Lori R. Roust ◽  
Christos S. Katsanos
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Function ◽  
Subcellular Location ◽  
Metabolic Dysfunction ◽  
Muscle Mitochondria ◽  
Skeletal Muscle Mitochondria ◽  
Experimental Approaches ◽  
And Function

Mitochondria from skeletal muscle of humans with obesity often display alterations with respect to their morphology, proteome, biogenesis, and function. These changes in muscle mitochondria are considered to contribute to metabolic abnormalities observed in humans with obesity. Most of the evidence describing alterations in muscle mitochondria in humans with obesity, however, lacks reference to a specific subcellular location. This is despite data over the years showing differences in the morphology and function of subsarcolemmal (found near the plasma membrane) and intermyofibrillar (nested between the myofibrils) mitochondria in skeletal muscle. Recent studies reveal that impairments in mitochondrial function in obesity with respect to the subcellular location of the mitochondria in muscle are more readily evident following exposure of the skeletal muscle to physiological stimuli. In this review, we highlight the need to understand skeletal muscle mitochondria metabolism in obesity in a subpopulation-specific manner and in the presence of physiological stimuli that modify mitochondrial function in vivo. Experimental approaches employed under these conditions will allow for more precise characterization of impairments in skeletal muscle mitochondria and their implications in inducing metabolic dysfunction in human obesity.

scholarly journals Phytochemical Nrf2 activator attenuates skeletal muscle mitochondrial dysfunction and impaired proteostasis in a preclinical model of musculoskeletal aging

2021 ◽  
Author(s):  
Robert V Musci ◽  
Kendra M Andrie ◽  
Maureen A Walsh ◽  
Zackary J Valenti ◽  
Maryam F Afzali ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Guinea Pigs ◽  
Muscle Protein ◽  
System Capacity ◽  
Related Factor ◽  
Age Related ◽  
Nrf2 Activator

Musculoskeletal dysfunction is an age-related syndrome associated with impaired mitochondrial function and proteostasis. However, few interventions have tested targeting two drivers of musculoskeletal decline. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that stimulates transcription of cytoprotective genes and improves mitochondrial function. We hypothesized daily treatment with a Nrf2 activator in Hartley guinea pigs, a model of age-related musculoskeletal dysfunction, attenuates the progression of skeletal muscle mitochondrial dysfunction and impaired proteostasis, preserving musculoskeletal function. We treated 2-month- and 5-month-old male and female Hartley guinea pigs for 3 and 10 months, respectively, with the phytochemical Nrf2 activator PB125 (Nrf2a). Longitudinal assessments of voluntary mobility were measured using Any-Maze™ open-field enclosure monitoring. Cumulative skeletal muscle protein synthesis rates were measured using deuterium oxide over the final 30 days of treatment. Mitochondrial oxygen consumption in permeabilized soleus muscles was measured using ex vivo high resolution respirometry. In both sexes, Nrf2a 1) increased electron transfer system capacity; 2) attenuated the disease/age-related decline in coupled and uncoupled mitochondrial respiration; and 3) attenuated declines in protein synthesis in the myofibrillar, mitochondrial, and cytosolic subfractions of the soleus. These improvements were not associated with statistically significant prolonged maintenance of voluntary mobility in guinea pigs. Collectively, these results demonstrate that treatment with an oral Nrf2 activator contributes to maintenance of skeletal muscle mitochondrial function and proteostasis in a pre-clinical model of musculoskeletal decline. Further investigation is necessary to determine if these improvements are also accompanied by slowed progression of other aspects of musculoskeletal decline.

scholarly journals A comparative study of mitochondrial respiration in circulating blood cells and skeletal muscle fibers in women

2019 ◽  
Vol 317 (3) ◽  
pp. E503-E512 ◽  
Author(s):  
Shannon Rose ◽  
Eugenia Carvalho ◽  
Eva C. Diaz ◽  
Matthew Cotter ◽  
Sirish C. Bennuri ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
Blood Cells ◽  
Muscle Fibers ◽  
Circulating Cells ◽  
Permeabilized Muscle

Skeletal muscle mitochondrial respiration is thought to be altered in obesity, insulin resistance, and type 2 diabetes; however, the invasive nature of tissue biopsies is an important limiting factor for studying mitochondrial function. Recent findings suggest that bioenergetics profiling of circulating cells may inform on mitochondrial function in other tissues in lieu of biopsies. Thus, we sought to determine whether mitochondrial respiration in circulating cells [peripheral blood mononuclear cells (PBMCs) and platelets] reflects that of skeletal muscle fibers derived from the same subjects. PBMCs, platelets, and skeletal muscle (vastus lateralis) samples were obtained from 32 young (25–35 yr) women of varying body mass indexes. With the use of extracellular flux analysis and high-resolution respirometry, mitochondrial respiration was measured in intact blood cells as well as in permeabilized cells and permeabilized muscle fibers. Respiratory parameters were not correlated between permeabilized muscle fibers and intact PBMCs or platelets. In a subset of samples ( n = 12–13) with permeabilized blood cells available, raw measures of substrate (pyruvate, malate, glutamate, and succinate)-driven respiration did not correlate between permeabilized muscle (per mg tissue) and permeabilized PBMCs (per 106 cells); however, complex I leak and oxidative phosphorylation coupling efficiency correlated between permeabilized platelets and muscle (Spearman’s ρ = 0.64, P = 0.030; Spearman’s ρ = 0.72, P = 0.010, respectively). Our data indicate that bioenergetics phenotypes in circulating cells cannot recapitulate muscle mitochondrial function. Select circulating cell bioenergetics phenotypes may possibly inform on overall metabolic health, but this postulate awaits validation in cohorts spanning a larger range of insulin resistance and type 2 diabetes status.

scholarly journals Uncoupled skeletal muscle mitochondria contribute to hypermetabolism in severely burned adults

2014 ◽  
Vol 307 (5) ◽  
pp. E462-E467 ◽  
Author(s):  
Craig Porter ◽  
David N. Herndon ◽  
Elisabet Børsheim ◽  
Tony Chao ◽  
Paul T. Reidy ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Metabolic Rate ◽  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
Citrate Synthase ◽  
Burn Patients ◽  
Muscle Mitochondria ◽  
Time Points ◽  
Burn Victims ◽  
Skeletal Muscle Mitochondria

Elevated metabolic rate is a hallmark of the stress response to severe burn injury. This response is mediated in part by adrenergic stress and is responsive to changes in ambient temperature. We hypothesize that uncoupling of oxidative phosphorylation in skeletal muscle mitochondria contributes to increased metabolic rate in burn survivors. Here, we determined skeletal muscle mitochondrial function in healthy and severely burned adults. Indirect calorimetry was used to estimate metabolic rate in burn patients. Quadriceps muscle biopsies were collected on two separate occasions (11 ± 5 and 21 ± 8 days postinjury) from six severely burned adults (68 ± 19% of total body surface area burned) and 12 healthy adults. Leak, coupled, and uncoupled mitochondrial respiration was determined in permeabilized myofiber bundles. Metabolic rate was significantly greater than predicted values for burn patients at both time points ( P < 0.05). Skeletal muscle oxidative capacity, citrate synthase activity, a marker of mitochondrial abundance, and mitochondrial sensitivity to oligomycin were all lower in burn patients vs. controls at both time points ( P < 0.05). A greater proportion of maximal mitochondrial respiration was linked to thermogenesis in burn patients compared with controls ( P < 0.05). Increased metabolic rate in severely burned adults is accompanied by derangements in skeletal muscle mitochondrial function. Skeletal muscle mitochondria from burn victims are more uncoupled, indicating greater heat production within skeletal muscle. Our findings suggest that skeletal muscle mitochondrial dysfunction contributes to increased metabolic rate in burn victims.

scholarly journals Mapping of the contraction-induced phosphoproteome identifies TRIM28 as a significant regulator of skeletal muscle size and function

Cell Reports ◽  
2021 ◽  
Vol 34 (9) ◽  
pp. 108796
Author(s):  
Nathaniel D. Steinert ◽  
Gregory K. Potts ◽  
Gary M. Wilson ◽  
Amelia M. Klamen ◽  
Kuan-Hung Lin ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Size ◽  
And Function

Exercise and Mitochondrial Function: Importance and InferenceA Mini Review

2021 ◽  
Vol 21 ◽  
Author(s):  
Vaishali K. ◽  
Nitesh Kumar ◽  
Vanishree Rao ◽  
Rakesh Krishna Kovela ◽  
Mukesh Kumar Sinha
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Function ◽  
Skeletal Muscles ◽  
Muscle Cells ◽  
Skeletal Muscle Cells ◽  
Present Review ◽  
Age Related ◽  
Exercise Induced ◽  
Mitochondrial Adaptations

: Skeletal muscles must generate and distribute energy properly in order to function perfectly. Mitochondria in skeletal muscle cells form vast networks to meet this need, and their functions may improve as a result of exercise. In the present review, we discussed exercise-induced mitochondrial adaptations, age-related mitochondrial decline, and a biomarker as a mitochondrial function indicator and exercise interference.

scholarly journals Dose Response of Endotoxin on Hepatocyte and Muscle Mitochondrial Respiration In Vitro

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Victor Jeger ◽  
Sebastian Brandt ◽  
Francesca Porta ◽  
Stephan M. Jakob ◽  
Jukka Takala ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Membrane Potential ◽  
Mitochondrial Respiration ◽  
Hepg2 Cells ◽  
Human Hepatocytes ◽  
Atp Content ◽  
Muscle Mitochondria ◽  
Complex Ii ◽  
Skeletal Muscle Mitochondria ◽  
Reduced Time

Introduction.Results on mitochondrial dysfunction in sepsis are controversial. We aimed to assess effects of LPS at wide dose and time ranges on hepatocytes and isolated skeletal muscle mitochondria.Methods.Human hepatocellular carcinoma cells (HepG2) were exposed to placebo or LPS (0.1, 1, and 10 μg/mL) for 4, 8, 16, and 24 hours and primary human hepatocytes to 1 μg/mL LPS or placebo (4, 8, and 16 hours). Mitochondria from porcine skeletal muscle samples were exposed to increasing doses of LPS (0.1–100 μg/mg) for 2 and 4 hours. Respiration rates of intact and permeabilized cells and isolated mitochondria were measured by high-resolution respirometry.Results.In HepG2 cells, LPS reduced mitochondrial membrane potential and cellular ATP content but did not modify basal respiration. Stimulated complex II respiration was reduced time-dependently using 1 μg/mL LPS. In primary human hepatocytes, stimulated mitochondrial complex II respiration was reduced time-dependently using 1 μg/mL LPS. In isolated porcine skeletal muscle mitochondria, stimulated respiration decreased at high doses (50 and 100 μg/mL LPS).Conclusion.LPS reduced cellular ATP content of HepG2 cells, most likely as a result of the induced decrease in membrane potential. LPS decreased cellular and isolated mitochondrial respiration in a time-dependent, dose-dependent and complex-dependent manner.

scholarly journals Superoxide Anion Production and Bioenergetic Profile in Young and Elderly Human Primary Myoblasts

2018 ◽  
Vol 2018 ◽  
pp. 1-16 ◽  
Author(s):  
Mariangela Marrone ◽  
Rita Maria Laura La Rovere ◽  
Simone Guarnieri ◽  
Ester Sara Di Filippo ◽  
Giovanni Monaco ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Oxidative Phosphorylation ◽  
Energy Demand ◽  
The Elderly ◽  
Compensatory Mechanisms ◽  
Superoxide Anion Production ◽  
Age Related ◽  
Primary Myoblasts ◽  
Production Variability ◽  
And Function

Sarcopenia is the age-related loss of skeletal muscle mass, strength, and function. It is associated with regenerative difficulties by satellite cells, adult muscle stem cells, and alteration of oxidative management, mainly the increase in superoxide anions (O2•−). We aimed to investigate the relation between regenerative deficit in elderly and increase in O2•− production along with mitochondrial alterations. Myoblasts and myotubes from skeletal muscle of young and elderly healthy subjects (27.8 ± 6 and 72.4 ± 6.5 years old) were measured: (1) superoxide dismutase activity and protein content, (2) mitochondrial O2•− production levels, (3) O2•− production variability, and (4) mitochondrial bioenergetic profile. Compared to young myoblasts, elderly myoblasts displayed decreased SOD2 protein expression, elevated mitochondrial O2•− baseline levels, and decreased oxidative phosphorylation and glycolysis. Additionally, elderly versus young myotubes showed elevated mitochondrial O2•− levels when stressed with N-acetyl cysteine or high glucose and higher glycolysis despite showing comparable oxidative phosphorylation levels. Altogether, the elderly may have less metabolic plasticity due to the impaired mitochondrial function caused by O2•−. However, the increased energy demand related to the differentiation process appears to activate compensatory mechanisms for the partial mitochondrial dysfunction.

Sign in / Sign up

Export Citation Format

Share Document