Abstract 16555: Angiotensin II Directly Induces Mitochondrial Dysfunction and Atrophy in the Skeletal Muscle

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Tomoyasu Kadoguchi ◽  
Shintaro Kinugawa ◽  
Arata Fukushima ◽  
Takaaki Furihata ◽  
Tadashi Suga ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Angiotensin Ii ◽  
Mitochondrial Dysfunction ◽  
Protein Degradation ◽  
Citrate Synthase ◽  
Fiber Type ◽  
Complex Iii ◽  
Skeletal Muscle Atrophy ◽  
Type I ◽  
Ang Ii

Background: Skeletal muscle abnormalities such as mitochondrial dysfunction, fiber type transition, and atrophy are the main cause of reduced exercise capacity observed in various diseases such as diabetes mellitus and heart failure. Renin-angiotensin system (RAS) was activated in the skeletal muscle in these conditions. We thus hypothesized that angiotensin II (Ang II) could directly induce skeletal muscle abnormalities. Methods and Results: Ang II (1000ng/kg/min, n=8) or vehicle (saline, n=8) was administrated into male C57BL/6J mice (10-12 week of age) via subcutaneously implanted osmotic minipumps for 4 weeks. Ang II significantly decreased body weight (26.6±0.3 vs. 27.6±0.3 g, p<0.05) and hind limb skeletal muscle weight compared with vehicle at 4 weeks (159±2 vs. 166±2 mg, p<0.05). It also decreased myocyte cross-sectional area in the skeletal muscle at 4 weeks (1869±29 vs. 2233±46 μm2, p<0.05). Muscle RING finger-1 and atrogin-1, the markers of protein degradation, were significantly increased in the skeletal muscle tissue from Ang II at 4 weeks by 133% and 102%, respectively (p<0.05). In addition, cleaved caspase-3 and TUNEL positive cells were significantly increased in Ang II at 4 weeks by 2.5 and 1.4-folds, respectively (p<0.05). Citrate synthase (1 week, 121±4 vs. 162±9; 4 weeks, 117±7 vs. 152±4 nmol/min/mg protein), complex I (1 week, 264±27 vs. 396±30; 4 weeks, 281±21 vs. 400±30 nmol/min/mg protein) and complex III (1 week, 321±33 vs. 508±49; 4 weeks, 347±30 vs. 503±43 nmol/min/mg protein) activities were significantly decreased in mitochondria isolated from skeletal muscle from Ang II at 1 and 4 weeks (all p<0.05). NADH staining revealed that type I fiber decreased by 31% and type IIb fiber increased by 38% in Ang II at 1 week. The work (16±1 vs. 27±3 J, p<0.05) and run distance (359±18 vs. 589±59 m, p<0.05) evaluated by treadmill test significantly decreased in Ang II at 4 weeks. An administration of Ang II for 1 week also induced mitochondrial dysfunction, fiber type shift, and protein degradation, but did not skeletal muscle atrophy. Conclusion: Ang II could directly induce the reduction of exercise tolerance in association with the abnormalities in skeletal muscle function and structure.

scholarly journals Fiber Composition and Oxidative Capacity of Hamster Skeletal Muscle

2002 ◽  
Vol 50 (12) ◽  
pp. 1685-1692 ◽  
Author(s):  
John P. Mattson ◽  
Todd A. Miller ◽  
David C. Poole ◽  
Michael D. Delp
Keyword(s):  
Skeletal Muscle ◽  
Citrate Synthase ◽  
Fiber Type ◽  
Rank Order ◽  
Oxidative Capacity ◽  
Type I ◽  
Cross Sectional ◽  
Physiological Investigation ◽  
Combining Data ◽  
Type I Fibers

The hamster is a valuable biological model for physiological investigation. Despite the obvious importance of the integration of cardiorespiratory and muscular system function, little information is available regarding hamster muscle fiber type and oxidative capacity, both of which are key determinants of muscle function. The purpose of this investigation was to measure immunohistochemically the relative composition and size of muscle fibers composed of types I, IIA, IIX, and IIB fibers in hamster skeletal muscle. The oxidative capacity of each muscle was also assessed by measuring citrate synthase activity. Twenty-eight hindlimb, respiratory, and facial muscles or muscle parts from adult (144–147 g bw) male Syrian golden hamsters ( n=3) were dissected bilaterally, weighed, and frozen for immunohistochemical and biochemical analysis. Combining data from all 28 muscles analyzed, type I fibers made up 5% of the muscle mass, type IIA fibers 16%, type IIX fibers 39%, and type IIB fibers 40%. Mean fiber cross-sectional area across muscles was 1665 ± 328 μm2 for type I fibers, 1900 ± 417 μm2 for type IIA fibers, 3230 ± 784 μm2 for type IIX fibers, and 4171 ± 864 μm2 for type IIB fibers. Citrate synthase activity was most closely related to the population of type IIA fibers ( r=0.68, p<0.0001) and was in the rank order of type IIA > I > IIX > IIB. These data demonstrate that hamster skeletal muscle is predominantly composed of type IIB and IIX fibers.

Type II skeletal myofibers possess unique properties that potentiate mitochondrial H2O2 generation

2006 ◽  
Vol 290 (3) ◽  
pp. C844-C851 ◽  
Author(s):  
Ethan J. Anderson ◽  
P. Darrell Neufer
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Dysfunction ◽  
Complex I ◽  
Basal Respiration ◽  
Superoxide Production ◽  
Complex Iii ◽  
Type I ◽  
Type Ii ◽  
Mitochondrial Content ◽  
Mitochondrial Superoxide

Mitochondrial dysfunction is implicated in a number of skeletal muscle pathologies, most notably aging-induced atrophy and loss of type II myofibers. Although oxygen-derived free radicals are thought to be a primary cause of mitochondrial dysfunction, the underlying factors governing mitochondrial superoxide production in different skeletal myofiber types is unknown. Using a novel in situ approach to measure H2O2 production (indicator of superoxide formation) in permeabilized rat skeletal muscle fiber bundles, we found that mitochondrial free radical leak (H2O2 produced/O2 consumed) is two- to threefold higher ( P < 0.05) in white (WG, primarily type IIB fibers) than in red (RG, type IIA) gastrocnemius or soleus (type I) myofibers during basal respiration supported by complex I (pyruvate + malate) or complex II (succinate) substrates. In the presence of respiratory inhibitors, maximal rates of superoxide produced at both complex I and complex III are markedly higher in RG and WG than in soleus muscle despite ∼50% less mitochondrial content in WG myofibers. Duplicate experiments conducted with ±exogenous superoxide dismutase revealed striking differences in the topology and/or dismutation of superoxide in WG vs. soleus and RG muscle. When normalized for mitochondrial content, overall H2O2 scavenging capacity is lower in RG and WG fibers, whereas glutathione peroxidase activity, which is largely responsible for H2O2 removal in mitochondria, is similar in all three muscle types. These findings suggest that type II myofibers, particularly type IIB, possess unique properties that potentiate mitochondrial superoxide production and/or release, providing a potential mechanism for the heterogeneous development of mitochondrial dysfunction in skeletal muscle.

Muscle protection during hibernation of Daurian ground squirrels (Spermophilus dauricus): role of atrogin-1, MuRF1, and fiber-type transition

2016 ◽  
Vol 94 (9) ◽  
pp. 619-629 ◽  
Author(s):  
Kai Dang ◽  
Ban Feng ◽  
Yunfang Gao ◽  
Naifei Hu ◽  
Shanfeng Jiang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mrna Expression ◽  
Muscle Atrophy ◽  
Hind Limb ◽  
Fiber Type ◽  
Ground Squirrels ◽  
Skeletal Muscle Atrophy ◽  
Type I ◽  
Protective Mechanisms ◽  
Edl Muscle

We investigated the mechanism of protection from skeletal muscle atrophy in the hind limb extensor digitorum longus (EDL) muscle of hibernating Daurian ground squirrels (Spermophilus dauricus Brandt, 1843). The effects of unrestrained hibernation and 14 day hind limb unloading (HLU) on EDL were studied in three seasons (summer, autumn, and winter). Atrogin-1 and MuRF1 mRNA skeletal muscle expression, wet muscle mass, and muscle to body mass ratios were unchanged during hibernation in all three seasons. EDL mass measurements decreased following HLU and atrogin-1 and MuRF1 mRNA expression increased. In summer, atrogin-1 and MuRF1 mRNA expression increased by 85% and 75%, respectively; in autumn, by 95% and 69%, respectively; and in winter, by 91% and 65%, respectively (P < 0.05). In the HLU group, microscopic skeletal muscle changes were present, including a reduction in the percentage of type-I skeletal muscle fibers. Fat storage in Daurian ground squirrels and a shorter photoperiod during hibernation did not affect the protective mechanisms that prevented skeletal muscle atrophy. The results of this study suggest that the stable expression of atrogin-1 and MuRF1 and the transition from fast glycolytic fibers to slow oxidative fibers are associated with a lack of skeletal muscle atrophy in the hibernating Daurian ground squirrel.

scholarly journals Skeletal muscle of females and males with constitutional thinness: a low intramuscular lipid content and oxidative profile

2020 ◽  
Vol 45 (11) ◽  
pp. 1287-1298 ◽  
Author(s):  
Mélina Bailly ◽  
Natacha Germain ◽  
Léonard Féasson ◽  
Frédéric Costes ◽  
Bruno Estour ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Weight Control ◽  
Glycogen Content ◽  
Citrate Synthase ◽  
Fiber Type ◽  
Muscle Fibers ◽  
Oxidative Capacity ◽  
Normal Weight ◽  
Type I ◽  
Before And After

Constitutional thinness (CT) is a nonpathological state of underweight. The current study aimed to explore skeletal muscle energy storage in individuals with CT and to further characterize muscle phenotype at baseline and in response to overfeeding. Thirty subjects with CT (15 females, 15 males) and 31 normal-weight control subjects (16 females, 15 males) participated in the study. Histological and enzymological analyses were performed on muscle biopsy specimens before and after overfeeding. In the skeletal muscle of CT participants compared with controls, we observed a lower content of intramuscular triglycerides for type I (−17%, p < 0.01) and type IIA (−14%, p < 0.05) muscle fibers, a lower glycogen content for type I (−6%, p < 0.01) and type IIA (−5%, p < 0.05) muscle fibers, a specific fiber-type distribution, a marked muscle hypotrophy (−20%, p < 0.001), a low capillary-to-fiber ratio (−19%, p < 0.001), and low citrate synthase activity (−18%, p < 0.05). In response to overfeeding, CT participants increased their intramuscular triglycerides content in type I (+10%, p < 0.01) and type IIA (+9%, p < 0.01) muscle fibers. CT individuals seem to present an unusual muscle phenotype and different adaptations to overfeeding compared with normal-weight individuals, suggesting a specific energy metabolism and muscle adaptations. ClinicalTrials.gov registration no. NCT02004821. Novelty Low intramuscular triglycerides and glycogen content in skeletal muscle of constitutionally thin individuals. Low oxidative capacity, low capillary supply, and fiber hypotrophy in skeletal muscle of constitutionally thin individuals. Increase in intramuscular triglycerides in constitutional thinness in response to overfeeding.

Skeletal muscle characteristics among distance runners: a 20-yr follow-up study

1995 ◽  
Vol 78 (3) ◽  
pp. 823-829 ◽  
Author(s):  
S. W. Trappe ◽  
D. L. Costill ◽  
W. J. Fink ◽  
D. R. Pearson
Keyword(s):  
Skeletal Muscle ◽  
Succinate Dehydrogenase ◽  
Citrate Synthase ◽  
Fiber Type ◽  
Type I ◽  
Distance Runners ◽  
Type Change ◽  
The Mean ◽  
Type I Fibers

The purpose of this investigation was to examine the histochemical and enzymatic characteristics of skeletal muscle after 20 yr of distance running training. Twenty-eight men were first studied between 1966 and 1974 when they were all highly trained distance runners. On the basis of their training regimens in the interim between testing, subjects were described as highly trained (HI; n = 11), fitness trained (FIT; n = 10), or untrained (UT; n = 7). Gastrocnemius muscle biopsy samples revealed a mean increase (P < 0.05) in the proportion of type I fibers of the FIT and UT groups, whereas the HI group, which was initially characterized by a high percentage (> 70%) of type I fibers, was unchanged. Although the mean fiber type change of the HI group was similar between evaluations, 6 of the 11 subjects did elicit an increase in the percentage of type I fibers. A subgroup of elite distance runners who had continued to train for competition experienced an approximately 25% reduction (P > 0.05) in muscle succinate dehydrogenase activity and decreases (P > 0.05) in types I and II muscle fiber areas. On the average, in 1993 the HI group had higher (P < 0.05) succinate dehydrogenase and citrate synthase activities than the FIT and UT groups, whereas phosphorylase activity did not differ among the three groups. These data suggest that the middle-aged men in this study had a significantly greater proportion of type I muscle fibers than when they were 20 yr younger.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Human and Rodent Skeletal Muscles Express Angiotensin II Type 1 Receptors

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1688
Author(s):  
Rafael Deminice ◽  
Hayden Hyatt ◽  
Toshinori Yoshihara ◽  
Mustafa Ozdemir ◽  
Branden Nguyen ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Angiotensin Ii ◽  
Muscle Atrophy ◽  
Muscle Fibers ◽  
Skeletal Muscle Atrophy ◽  
Type I ◽  
Single Muscle ◽  
Rat Skeletal Muscle ◽  
Skeletal Muscle Fibers

Abundant evidence reveals that activation of the renin-angiotensin system promotes skeletal muscle atrophy in several conditions including congestive heart failure, chronic kidney disease, and prolonged mechanical ventilation. However, controversy exists about whether circulating angiotensin II (AngII) promotes skeletal muscle atrophy by direct or indirect effects; the centerpiece of this debate is the issue of whether skeletal muscle fibers express AngII type 1 receptors (AT1Rs). While some investigators assert that skeletal muscle expresses AT1Rs, others argue that skeletal muscle fibers do not contain AT1Rs. These discordant findings in the literature are likely the result of study design flaws and additional research using a rigorous experimental approach is required to resolve this issue. We tested the hypothesis that AT1Rs are expressed in both human and rat skeletal muscle fibers. Our premise was tested using a rigorous, multi-technique experimental design. First, we established both the location and abundance of AT1Rs on human and rat skeletal muscle fibers by means of an AngII ligand-binding assay. Second, using a new and highly selective AT1R antibody, we carried out Western blotting and determined the abundance of AT1R protein within isolated single muscle fibers from humans and rats. Finally, we confirmed the presence of AT1R mRNA in isolated single muscle fibers from rats. Our results support the hypothesis that AT1Rs are present in both human and rat skeletal muscle fibers. Moreover, our experiments provide the first evidence that AT1Rs are more abundant in fast, type II muscle fibers as compared with slow, type I fibers. Together, these discoveries provide the foundation for an improved understanding of the mechanism(s) responsible for AngII-induced skeletal muscle atrophy.

Lower citrate synthase activity, mitochondrial complex expression, and fewer oxidative myofibers characterize skeletal muscle from growth restricted fetal sheep

2021 ◽  
Author(s):  
Jane Stremming ◽  
Eileen Chang ◽  
Leslie A Knaub ◽  
Michael L Armstrong ◽  
Peter R Baker ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Oxidative Metabolism ◽  
Mitochondrial Respiration ◽  
Citrate Synthase ◽  
Fiber Type ◽  
Late Gestation ◽  
Postnatal Life ◽  
Type I ◽  
Mitochondrial Complex ◽  
Fetal Sheep

Skeletal muscle from the late gestation sheep fetus with intrauterine growth restriction (IUGR) has evidence of reduced oxidative metabolism. Using a sheep model of placental insufficiency and IUGR, we tested the hypothesis that by late gestation, IUGR fetal skeletal muscle has reduced capacity for oxidative phosphorylation due to intrinsic deficits in mitochondrial respiration. We measured mitochondrial respiration in permeabilized muscle fibers from biceps femoris (BF) and soleus (SOL) from control and IUGR fetal sheep. Using muscles including BF, SOL, tibialis anterior (TA), and flexor digitorum superficialis (FDS), we measured citrate synthase (CS) activity, mitochondrial complex subunit abundance, fiber type distribution, and gene expression of regulators of mitochondrial biosynthesis. Ex vivo mitochondrial respiration was similar in control and IUGR muscle. However, CS activity was lower in IUGR BF and TA, indicating lower mitochondrial content, and protein expression of individual mitochondrial complex subunits was lower in IUGR TA and BF in a muscle specific pattern. IUGR TA, BF, and FDS also had lower expression of type I oxidative fibers. Fiber type shifts that support glycolytic instead of oxidative metabolism may be advantageous for the IUGR fetus in a hypoxic and nutrient deficient environment, whereas these adaptions may be maladaptive in postnatal life.

Abstract 15506: Inhibition of Angiotensin II Type I Receptor Induces Dual Modification of Mitochondrial Dynamics and Mitophagy via Inactivation of Ras/raf/mek Pathway and Contributes Vascular Anti-senescence

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Yoshihiro Uchikado ◽  
Yoshiyuki Ikeda ◽  
Yuichi Sasaki ◽  
Yuichi Akasaki ◽  
Mitsuru Ohishi
Keyword(s):  
Angiotensin Ii ◽  
Mitochondrial Dysfunction ◽  
Cellular Senescence ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Type I ◽  
Ang Ii ◽  
Double Knockout ◽  
Apoe Ko ◽  
Vascular Senescence

Introduction: Angiotensin II (Ang II) causes vascular senescence by damaging mitochondria that undergo quality control by mitochondrial dynamics and mitophagy. We examined whether and how AngII type I receptor (AT1R) signal regulates mitochondrial dynamics and mitophagy in the etiology of vascular senescence. Methods: We used vascular smooth muscle cells (VSMC) and C57BL6 (WT), apolipoprotein E deficient (ApoE KO) and the double knockout of ApoE and AT1R mice. Results: Administration of Ang II to VSMC forced mitochondria to fission and induced cellular senescence and mitochondrial dysfunction, which were restored by inhibition of fission by use of Mdivi-1. Treatment of ox-LDL also induced cellular senescence accompanied by excessive mitochondrial fission through phosphorylation of Drp1 at Ser616 and mitochondrial dysfunction. These alterations were ameliorated by inhibition of AT1R signal, suggesting that AT1R signal inhibition may contribute anti-cellular senescence by modification of mitochondrial dynamics. AT1R signal inhibition also induced mitophagy assessed by electron microscopy and immunohistochemistry of LAMP2 and TOMM20. AT1R inhibition-induced mitophagy was not affected by Atg7 Knockdown, whereas it was diminished by Rab9 knockdown. Immunohistochemistry showed TOMM20 dots were co-localized to LAMP2 and Rab9 but not LC3. These results suggest that AT1R signal induces mitophagy derived from Rab9-dependent alternative autophagy. Treatment of ox-LDL activated Ras, Raf and MEK, and AT1R inhibition inactivated them. Inhibition of Ras/Raf/MEK decreased excessive mitochondrial fission and induced mitophagy, suggesting that AT1R signal followed by Ras/Raf/MEK pathway modulates both mitochondrial dynamics and mitophagy. The degree of arterial senescence and atherosclerosis, Drp1 expression in mitochondrial fraction and oxidative stress in artery were higher and the number of mitophagy, fused mitochondria and its function were lower in ApoE KO than those of WT mice. AT1R KO to ApoE KO attenuated these adverse effects of ApoE KO. Conclusions: Inhibition of AT1R signal contributes vascular senescence through modification of mitochondrial dynamics and mitophagy by inactivation of Ras/Raf/MEK pathway.

Diabetic myopathy differs betweenIns2Akita+/−and streptozotocin-induced Type 1 diabetic models

2009 ◽  
Vol 106 (5) ◽  
pp. 1650-1659 ◽  
Author(s):  
Matthew P. Krause ◽  
Michael C. Riddell ◽  
Carly S. Gordon ◽  
S. Abdullah Imam ◽  
Enzo Cafarelli ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Citrate Synthase ◽  
Genetic Model ◽  
Fiber Type ◽  
Type I ◽  
Phenotypic Properties ◽  
Current State ◽  
Type I Fibers

Mechanistic studies examining the effects of Type 1 diabetes mellitus (T1DM) on skeletal muscle have largely relied on streptozotocin-induced diabetic (STZ) rodents. Unfortunately, characterization of diabetic myopathy in this model is confounded by the effects of streptozotocin on skeletal muscle independent of the diabetic phenotype. Here we define adolescent diabetic myopathy in a novel, genetic model of T1DM, Ins2Akita+/−mice, and contrast these findings with STZ mice. Eight weeks of diabetes resulted in significantly reduced gastrocnemius-plantaris-soleus mass (control: 0.16 ± 0.005 g; Ins2Akita+/−: 0.12 ± 0.003 g; STZ: 0.12 ± 0.01g) and IIB/D fiber area in Ins2Akita+/−(1,294 ± 94 μm2) and STZ (1,768 ± 163 μm2) compared with control (2,241 ± 144 μm2). Conversely, STZ type I fibers (1,535 ± 165 μm2) were significantly larger than Ins2Akita+/−(915 ± 76 μm2) but not control (1,152 ± 86 μm2). Intramyocellular lipid increased in STZ (122.9 ± 3.6% of control) but not Ins2Akita+/−likely resultant from depressed citrate synthase (control: 6.2 ± 1.2 μmol·s−1·mg−1; Ins2Akita+/−: 5.2 ± 0.8 μmol·s−1·mg−1; STZ: 2.8 ± 0.5 μmol·s−1·mg−1) and 3-β-hydroxyacyl coenzyme-A dehydrogenase (control: 4.2 ± 0.6 nmol·s−1·mg−1; Ins2Akita+/−: 5.0 ± 0.6 nmol·s−1·mg−1; STZ: 2.7 ± 0.6 nmol·s−1·mg−1) enzyme activity in STZ muscle. In situ muscle stimulation revealed lower absolute peak tetanic force in Ins2Akita+/−(70.2 ± 8.2% of control) while STZ exhibited an insignificant decrease (87.6 ± 7.9% of control). Corrected for muscle mass, no force loss was observed in Ins2Akita+/−, while STZ was significantly elevated vs. control and Ins2Akita+/−. These results demonstrate that atrophy and specific fiber-type loss in Ins2Akita+/−muscle did not affect contractile properties (relative to muscle mass). Furthermore, we demonstrate distinctive contractile, metabolic, and phenotypic properties in STZ vs. Ins2Akita+/−diabetic muscle despite similarity in hyperglycemia/hypoinsulinemia, raising concerns of our current state of knowledge regarding the effects of T1DM on skeletal muscle.

scholarly journals Physiology of a Microgravity Environment Invited Review: Microgravity and skeletal muscle

2000 ◽  
Vol 89 (2) ◽  
pp. 823-839 ◽  
Author(s):  
Robert H. Fitts ◽  
Danny R. Riley ◽  
Jeffrey J. Widrick
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Thin Filament ◽  
Molecular Mechanisms ◽  
Skeletal Muscle Atrophy ◽  
Microgravity Environment ◽  
Type I ◽  
Fiber Types ◽  
Maximal Velocity ◽  
Cross Sectional

Spaceflight (SF) has been shown to cause skeletal muscle atrophy; a loss in force and power; and, in the first few weeks, a preferential atrophy of extensors over flexors. The atrophy primarily results from a reduced protein synthesis that is likely triggered by the removal of the antigravity load. Contractile proteins are lost out of proportion to other cellular proteins, and the actin thin filament is lost disproportionately to the myosin thick filament. The decline in contractile protein explains the decrease in force per cross-sectional area, whereas the thin-filament loss may explain the observed postflight increase in the maximal velocity of shortening in the type I and IIa fiber types. Importantly, the microgravity-induced decline in peak power is partially offset by the increased fiber velocity. Muscle velocity is further increased by the microgravity-induced expression of fast-type myosin isozymes in slow fibers (hybrid I/II fibers) and by the increased expression of fast type II fiber types. SF increases the susceptibility of skeletal muscle to damage, with the actual damage elicited during postflight reloading. Evidence in rats indicates that SF increases fatigability and reduces the capacity for fat oxidation in skeletal muscles. Future studies will be required to establish the cellular and molecular mechanisms of the SF-induced muscle atrophy and functional loss and to develop effective exercise countermeasures.

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