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At least 73 records · Page 4

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NASA NTRS2001

Time course of the MAPK and PI3-kinase response within 24 h of skeletal muscle overload

Knowledge of the molecular mechanisms by which skeletal muscle hypertrophies in response to increased mechanical loading may lead to the discovery of novel treatment strategies for muscle wasting and frailty. To gain insight into potential early signaling mechanisms associated with skeletal muscle hypertrophy, the temporal pattern of mitogen-activated protein kinase (MAPK) phosphorylation and phosphatidylinositol 3-kinase (PI3-kinase) activity during the first 24 h of muscle overload was determined in the rat slow-twitch soleus and fast-twitch plantaris muscles after ablation of the gastrocnemius muscle. p38alpha MAPK phosphorylation was elevated for the entire 24-h overload period in both muscles. In contrast, Erk 2 and p54 JNK phosphorylation were transiently increased by overload, returning to the levels of sham-operated controls by 24 h. PI3-kinase activity was increased by muscle overload only at 12 h of overload and only in the plantaris muscle. In summary, sustained elevation of p38alpha MAPK phosphorylation occurred early in response to muscle overload, identifying this pathway as a potential candidate for mediating early hypertrophic signals in response to skeletal muscle overload.

Non-NASA Center↗

NASA NTRS1998

Sympathetic activation in exercise is not dependent on muscle acidosis. Direct evidence from studies in metabolic myopathies

Muscle acidosis has been implicated as a major determinant of reflex sympathetic activation during exercise. To test this hypothesis we studied sympathetic exercise responses in metabolic myopathies in which muscle acidosis is impaired or augmented during exercise. As an index of reflex sympathetic activation to muscle, microneurographic measurements of muscle sympathetic nerve activity (MSNA) were obtained from the peroneal nerve. MSNA was measured during static handgrip exercise at 30% of maximal voluntary contraction force to exhaustion in patients in whom exercise-induced muscle acidosis is absent (seven myophosphorylase deficient patients; MD [McArdle's disease], and one patient with muscle phosphofructokinase deficiency [PFKD]), augmented (one patient with mitochondrial myopathy [MM]), or normal (five healthy controls). Muscle pH was monitored by 31P-magnetic resonance spectroscopy during handgrip exercise in the five control subjects, four MD patients, and the MM and PFKD patients. With handgrip to exhaustion, the increase in MSNA over baseline (bursts per minute [bpm] and total activity [%]) was not impaired in patients with MD (17+/-2 bpm, 124+/-42%) or PFKD (65 bpm, 307%), and was not enhanced in the MM patient (24 bpm, 131%) compared with controls (17+/-4 bpm, 115+/-17%). Post-handgrip ischemia studied in one McArdle patient, caused sustained elevation of MSNA above basal suggesting a chemoreflex activation of MSNA. Handgrip exercise elicited an enhanced drop in muscle pH of 0.51 U in the MM patient compared with the decrease in controls of 0.13+/-0.02 U. In contrast, muscle pH increased with exercise in MD by 0.12+/-0.05 U and in PFKD by 0.01 U. In conclusion, patients with glycogenolytic, glycolytic, and oxidative phosphorylation defects show normal muscle sympathetic nerve responses to static exercise. These findings indicate that muscle acidosis is not a prerequisite for sympathetic activation in exercise.

NASA Discipline Cardiopulmonary↗

NASA NTRS2003

Interactions between neutrophils and macrophages promote macrophage killing of rat muscle cells in vitro

Current evidence indicates that the physiological functions of inflammatory cells are highly sensitive to their microenvironment, which is partially determined by the inflammatory cells and their potential targets. In the present investigation, interactions between neutrophils, macrophages and muscle cells that may influence muscle cell death are examined. Findings show that in the absence of macrophages, neutrophils kill muscle cells in vitro by superoxide-dependent mechanisms, and that low concentrations of nitric oxide (NO) protect against neutrophil-mediated killing. In the absence of neutrophils, macrophages kill muscle cells through a NO-dependent mechanism, and the presence of target muscle cells causes a three-fold increase in NO production by macrophages, with no change in the concentration of inducible nitric oxide synthase. Muscle cells that are co-cultured with both neutrophils and macrophages in proportions that are observed in injured muscle show cytotoxicity through a NO-dependent, superoxide-independent mechanism. Furthermore, the concentration of myeloid cells that is necessary for muscle killing is greatly reduced in assays that use mixed myeloid cell populations, rather than uniform populations of neutrophils or macrophages. These findings collectively show that the magnitude and mechanism of muscle cell killing by myeloid cells are modified by interactions between muscle cells and neutrophils, between muscle cells and macrophages and between macrophages and neutrophils.

Non-NASA Center↗

NASA NTRS1995

Activation of the ATP-ubiquitin-proteasome pathway in skeletal muscle of cachectic rats bearing a hepatoma

Rats implanted with Yoshida ascites hepatoma (YAH) show a rapid and selective loss of muscle protein due mainly to a marked increase (63-95%) in the rate of protein degradation (compared with rates in muscles of pair-fed controls). To define which proteolytic pathways contribute to this increase, epitrochlearis muscles from YAH-bearing and control rats were incubated under conditions that modify different proteolytic systems. Overall proteolysis in either group of rats was not affected by removal of Ca2+ or by blocking the Ca(2+)-dependent proteolytic system. Inhibition of lysosomal function with methylamine reduced proteolysis (-12%) in muscles from YAH-bearing rats, but not in muscles of pair-fed rats. When ATP production was also inhibited, the remaining accelerated proteolysis in muscles of tumor-bearing rats fell to control levels. Muscles of YAH-bearing rats showed increased levels of ubiquitin-conjugated proteins and a 27-kDa proteasome subunit in Western blot analysis. Levels of mRNA encoding components of proteolytic systems were quantitated using Northern hybridization analysis. Although their total RNA content decreased 20-38%, pale muscles of YAH-bearing rats showed increased levels of ubiquitin mRNA (590-880%) and mRNA for multiple subunits of the proteasome (100-215%). Liver, kidney, heart, and brain showed no weight loss and no change in these mRNA species. Muscles of YAH-bearing rats also showed small increases (30-40%) in mRNA for cathepsins B and D, but not for calpain I or heat shock protein 70. Our findings suggest that accelerated muscle proteolysis and muscle wasting in tumor-bearing rats result primarily from activation of the ATP-dependent pathway involving ubiquitin and the proteasome.

NASA Discipline Musculoskeletal↗

NASA NTRS2014

A Mathematical Model of Oxygen Transport in Skeletal Muscle During Hindlimb Unloading

During hindlimb unloading (HU) dramatic fluid shifts occur within minutes of the suspension, leading to a less precise matching of blood flow to O2 demands of skeletal muscle. Vascular resistance directs blood away from certain muscles, such as the soleus (SOL). The muscle volume gradually reduces in these muscles so that eventually the relative blood flow returns to normal. It is generally believed that muscle volume change is not due to O2 depletion, but a consequence of disuse. However, the volume of the unloaded rat muscle declines over the course of weeks, whereas the redistribution of blood flow occurs immediately. Using a Krogh Cylinder Model, the distribution of O2 was predicted in two skeletal muscles: SOL and gastrocnemius (GAS). Effects of the muscle blood flow, volume, capillary density, and O2 uptake, are included to calculate the pO2 at rest and after 10 min and 15 days of unloading. The model predicts that 32 percent of the SOL muscle tissue has a pO2 1.25 mm Hg within 10 min, whereas the GAS maintains normal O2 levels, and that equilibrium is reached only as the SOL muscle cells degenerate. The results provide evidence that there is an inadequate O2 supply to the mitochondria in the SOL muscle after 10 min HU.

Mathematical models↗

DOE OSTI2026

Arm and shoulder muscle segmentation in axial MRI with UNet deep learning model

Quantifying individual upper-limb muscle volumes from MRI provides key insight into muscle-specific strength, deficits, and adaptations. Manual delineation is the gold standard but time‑intensive, and the performance of current deep learning approaches, particularly for small or anatomically complex muscles, remains incompletely characterized. We evaluated a state‑of‑the‑art deep learning framework across the entire upper limb and analyzed factors governing segmentation performance, with attention to the forearm. Three previously published MRI datasets (1.5 T, 3D GRE T1‑weighted; total n = 39) spanning young, middle‑aged, and older adults were curated and quality‑checked, including expert manual segmentations for 31 muscles. Following multiclass mask reconstruction, we trained three 3D nnU‑Net multiclass models matched to the muscle subsets present across datasets, using five‑fold cross‑validation and a composite Dice Similarity Coefficient (DSC) + cross entropy loss. Segmentation accuracy was assessed with DSC. Performance varied across muscles (mean DSC = 0.806 ± 0.098), ranging from 0.920 (Deltoid) to 0.461 (Extensor pollicis brevis). In uncertainty‑weighted regressions, muscle volume was positively associated with DSC (R2 = 0.36, p < 0.001), whereas training segmentation count and muscle orientation showed negligible associations (R2 ≤ 0.06). A weighted mixed‑effects model identified volume as the strongest evaluated predictor, explaining 23.9% of variance in DSC; orientation and training count each contributed <1%, leaving 61.5% unexplained. These results indicate that deep learning–based segmentation can accurately quantify muscle volume for many upper‑limb muscles but remains constrained for small, low‑contrast forearm muscles.

Gillespie, Samuel↗

NASA NTRS1980

The effects of cutting or of stretching skeletal muscle in vitro on the rates of protein synthesis and degradation

Skeletal muscle preparations using cut muscle fibers have often been used in studies of protein metabolism. The present paper reports an investigation of the effect of muscle cutting or stretching in vitro on the rates of protein synthesis and/or degradation. Protein synthesis and content, and ATP and phosphocreatine levels were monitored in soleus and extensor digitorum longus muscles from the rat with various extents of muscle fiber cuts and following stretching to about 120% the resting length. Rates of protein synthesis are found to be significantly lower and protein degradation higher in the cut muscles than in uncut controls, while ATP and phosphocreatine concentrations decreased. Stretched intact muscles, on the other hand, are observed to have higher concentrations of high-energy phosphates than unstretched muscles, while rates of protein degradation were not affected. Results thus demonstrate that the cutting of skeletal muscle fibers alters many aspects of muscle metabolism, and that moderate decreases in ATP concentration do not alter rates of protein concentration in intact muscles in vitro.

Seider, M. J.↗

NASA NTRS1999

Effect of Electrical Stimulation on Beta-Adrenergic Receptor Population and Coupling Efficiency in Chicken and Rat Skeleton Muscle Cell Cultures

Expression of the beta-adrenergic receptor (bAR) and its coupling to cyclic AMP (cAMP) synthesis are important components of the signaling system that controls muscle atrophy and hypertrophy, and the goal of this study was to determine if electrical stimulation in a pattern simulating slow muscle contraction would alter the bAR response in primary cultures of avian and mammalian skeletal muscle cells. Specifically, chicken skeletal muscle cells and rat skeletal muscle cells that had been grown for seven days in culture were subjected to electrical stimulation for an additional two days at a pulse frequency of 0.5 pulses/sec and a pulse duration of 200 msec. In chicken skeletal muscle cells, the bAR population was not significantly affected by electrical stimulation; however, the ability of these cells to synthesize cyclic AMP was reduced by approximately one-half. Thus, in chicken muscle cells an enhanced level of contraction reduced the coupling efficiency of bAR for cyclic AMP production by approximately 55% compared to controls. In contrast, the bAR population in rat muscle cells was increased by approximately 25% by electrical stimulation, and the ability of these cells to synthesize cyclic AMP was also increased by almost two-fold. Thus, in rat muscle cells an enhanced level of contraction increased the coupling efficiency of bAR for cyclic AMP production by approximately 50% compared to controls. The basal levels of intracellular cyclic AMP in both rat muscle cells and chicken muscle cells were not affected by electrical stimulation.

Young, Ronald B.↗

NASA NTRS1998

The Toll pathway is required in the epidermis for muscle development in the Drosophila embryo

The Toll signaling pathway functions in several Drosophila processes, including dorsal-ventral pattern formation and the immune response. Here, we demonstrate that this pathway is required in the epidermis for proper muscle development. Previously, we showed that the zygotic Toll protein is necessary for normal muscle development; in the absence of zygotic Toll, close to 50% of hemisegments have muscle patterning defects consisting of missing, duplicated and misinserted muscle fibers (Halfon, M.S., Hashimoto, C., and Keshishian, H., Dev. Biol. 169, 151-167, 1995). We have now also analyzed the requirements for easter, spatzle, tube, and pelle, all of which function in the Toll-mediated dorsal-ventral patterning pathway. We find that spatzle, tube, and pelle, but not easter, are necessary for muscle development. Mutations in these genes give a phenotype identical to that seen in Toll mutants, suggesting that elements of the same pathway used for Toll signaling in dorsal-ventral development are used during muscle development. By expressing the Toll cDNA under the control of distinct Toll enhancer elements in Toll mutant flies, we have examined the spatial requirements for Toll expression during muscle development. Expression of Toll in a subset of epidermal cells that includes the epidermal muscle attachment cells, but not Toll expression in the musculature, is necessary for proper muscle development. Our results suggest that signals received by the epidermis early during muscle development are an important part of the muscle patterning process.

Non-NASA Center↗

NASA NTRS2009

Muscle Volume Increases Following 16 Weeks of Resistive Exercise Training with the Advanced Resistive Exercise Device (ARED) and Free Weights

Space flight-induced muscle atrophy, particularly in the postural and locomotorymuscles, may impair task performance during long-duration space missions and planetary exploration. High intensity free weight (FW) resistive exercise training has been shown to prevent atrophy during bed rest, a space flight analog. NASA developed the Advanced Resistive Exercise Device (ARED) to simulate the characteristics of FW exercise (i.e. constant mass, inertial force) and to be used as a countermeasure during International Space Station (ISS) missions. PURPOSE: To compare the efficacy of ARED and FW training to induce hypertrophy in specific muscle groups in ambulatory subjects prior to deploying ARED on the ISS. METHODS: Twenty untrained subjects were assigned to either the ARED (8 males, 3 females) or FW (6 males, 3 females) group and participated in a periodizedtraining protocol consisting of squat (SQ), heel raise (HR), and deadlift(DL) exercises 3 d wk-1 for 16 wks. SQ, HR, and DL muscle strength (1RM) was measured before, after 8 wks, and after 16 wks of training to prescribe exercise and measure strength changes. Muscle volume of the vastigroup (V), hamstring group (H), hip adductor group (ADD), medial gastrocnemius(MG), lateral gastrocnemius(LG), and deep posterior muscles including soleus(DP) was measured using MRI pre-and post-training. Consecutive cross-sectional images (8 mm slices with a 2 mm gap) were analyzed and summed. Anatomical references insured that the same muscle sections were analyzed pre-and post-training. Two-way repeated measures ANOVAs (p<0.05) were used to test for differences in muscle strength and volume between training devices. RESULTS: SQ, HR, and DL 1RM increased in both FW (SQ: 49+/-6%, HR: 12+/-2%, DL: 23+/-4%) and ARED (SQ: 31+/-4%, HR: 18+/-2%, DL: 23+/-3%) groups. Both groups increased muscle volume in the V (FW: 13+/-2%, ARED: 10+/-2%), H (FW: 3+/-1%, ARED: 3+/-1 %), ADD (FW: 15=/-2%, ARED: 10+/-1%), LG (FW: 7+/-2%, ARED: 4+/-1%), MG (FW: 7+/-2%, ARED: 5+/-2%), and DP (FW: 2+/-1%; ARED: 2+/-1%) after training. There were no between group differences in muscle strength or volume. CONCLUSIONS: The increase in muscle volume and strength following ARED training is not different than FW training. With the training effects similar to FW and a 600 lb load capacity, ARED likely will protect against muscle atrophy in microgravity.

Nash, R. E.↗

NASA NTRS2014

Exposure to Microgravity for 30 Days Onboard Bion M1 Caused Muscle Atrophy and Decreased Regeneration in the Mouse Femoral Quadriceps

Mechanical unloading of muscle during spaceflight in microgravity is known to cause muscular atrophy, changes in muscle fiber type composition, gene expression, and reductions in regenerative muscle growth. Although limited data exists for long-term effects of microgravity in human muscle, these processes have mostly been studied in rodents for short periods of time. Here we report on how 30-day, long-term, mechanical unloading in microgravity affects mouse muscle of the femoral Quadriceps group. To conduct these studies we used muscle tissue from 6 mice from the NASA Biospecimen Sharing Program conducted in collaboration with the Institute for Biomedical Problems of the Russian Academy of Sciences, during the Russian Bion M1 biosatellite mission in 2013. Muscle morphology observed in histological sections shows signs of extensive atrophy and regenerative hypoplasia. Specifically, we observed a two-fold decrease in the number of myonuclei, their central location, low density of myofibers and myofibrils, in fragmentation and swelling of myofibers. Despite obvious atrophy, muscle regeneration nevertheless appears to have continued after 30 days in microgravity as evidenced by thin and short newly formed myofibers. Many of them however showed evidence of apoptotic, TUNEL positive cells and myofibrils degradation, suggesting long-term unloading in microgravity affects late stages of myofiber differentiation. Ground asynchronous and vivarium control animals showed normal, well-developed tissue structure with sufficient blood and nerve supply and evidence of regenerative formation of new myofibers free of apoptotic nuclei. Myonuclei stress response in spaceflight animals was detected by positive nuclear immunolocalization of c-jun and c-myc proteins. Regenerative activity of satellite cells in muscles is detected in mice of all animal groups, by pax7, MyoD, and myogenin immunostaining and myogenin PCR analysis. In summary, long-term spaceflight in microgravity causes significant atrophy and degeneration of the femoral Quadriceps muscle group, and it may interfere with muscle regenerative processes by inducing apoptosis in newly-formed myofibrils during their differentiation phase.

Grigoryan, E. N.↗

NASA NTRS2001

ANG II is required for optimal overload-induced skeletal muscle hypertrophy

ANG II mediates the hypertrophic response of overloaded cardiac muscle, likely via the ANG II type 1 (AT(1)) receptor. To examine the potential role of ANG II in overload-induced skeletal muscle hypertrophy, plantaris and/or soleus muscle overload was produced in female Sprague-Dawley rats (225-250 g) by the bilateral surgical ablation of either the synergistic gastrocnemius muscle (experiment 1) or both the gastrocnemius and plantaris muscles (experiment 2). In experiment 1 (n = 10/group), inhibiting endogenous ANG II production by oral administration of an angiotensin-converting enzyme (ACE) inhibitor during a 28-day overloading protocol attenuated plantaris and soleus muscle hypertrophy by 57 and 96%, respectively (as measured by total muscle protein content). ACE inhibition had no effect on nonoverloaded (sham-operated) muscles. With the use of new animals (experiment 2; n = 8/group), locally perfusing overloaded soleus muscles with exogenous ANG II (via osmotic pump) rescued the lost hypertrophic response in ACE-inhibited animals by 71%. Furthermore, orally administering an AT(1) receptor antagonist instead of an ACE inhibitor produced a 48% attenuation of overload-induced hypertrophy that could not be rescued by ANG II perfusion. Thus ANG II may be necessary for optimal overload-induced skeletal muscle hypertrophy, acting at least in part via an AT(1) receptor-dependent pathway.

NASA Discipline Musculoskeletal↗

NASA NTRS1999

Skeletal muscle myostatin mRNA expression is fiber-type specific and increases during hindlimb unloading

Transgenic mice lacking a functional myostatin (MSTN) gene demonstrate greater skeletal muscle mass resulting from muscle fiber hypertrophy and hyperplasia (McPherron, A. C., A. M. Lawler, and S. -J. Lee. Nature 387: 83-90, 1997). Therefore, we hypothesized that, in normal mice, MSTN may act as a negative regulator of muscle mass. Specifically, we hypothesized that the predominately slow (type I) soleus muscle, which demonstrates greater atrophy than the fast (type II) gastrocnemius-plantaris complex (Gast/PLT), would show more elevation in MSTN mRNA abundance during hindlimb unloading (HU). Surprisingly, MSTN mRNA was not detectable in weight-bearing or HU soleus muscle, which atrophied 42% by the 7th day of HU in female ICR mice. In contrast, MSTN mRNA was present in weight-bearing Gast/PLT muscle and was significantly elevated (67%) at 1 day but not at 3 or 7 days of HU. However, the Gast/PLT muscle had only atrophied 17% by the 7th day of HU. Because the soleus is composed only of type I and IIa fibers, whereas the Gast/PLT expresses type IId/x and IIb in addition to type I and IIa, it was necessary to perform a more careful analysis of the relationship between MSTN mRNA levels and myosin heavy-chain (MHC) isoform expression (as a marker of fiber type). A significant correlation (r = 0.725, P < 0. 0005) was noted between the percentage of MHC isoform IIb expression and MSTN mRNA abundance in several muscles of the mouse hindlimb. These results indicate that MSTN expression is not strongly associated with muscle atrophy induced by HU; however, it is strongly associated with MHC isoform IIb expression in normal muscle.

Non-NASA Center↗

NASA NTRS1997

Molecular events underlying skeletal muscle atrophy and the development of effective countermeasures

Skeletal muscle adapts to loading; atrophying when exposed to unloading on Earth or in spaceflight. Significant atrophy (decreases in muscle fiber cross-section of 11-24%) in humans has been noted after only 5 days in space. Since muscle strength is determined both by muscle cross-section and synchronization of motor unit recruitment, a loss in muscle size weakens astronauts, which would increase risks to their safety if an emergency required maximal muscle force. Numerous countermeasures have been tested to prevent atrophy. Resistant exercise together with growth hormone and IGF-I are effective countermeasures to unloading as most atrophy is prevented in animal models. The loss of muscle protein is due to an early decrease in protein synthesis rate and a later increase in protein degradation. The initial decrease in protein synthesis is a result of decreased protein translation, caused by a prolongation in the elongation rate. A decrease in HSP70 by a sight increase in ATP may be the factors prolonging elongation rate. Increases in the activities of proteolytic enzymes and in ubiquitin contribute to the increased protein degradation rate in unloaded muscle. Numerous mRNA concentrations have been shown to be altered in unloaded muscles. Decreases in mRNAs for contractile proteins usually occur after the initial fall in protein synthesis rates. Much additional research is needed to determine the mechanism by which muscle senses the absence of gravity with an adaptive atrophy. The development of effective countermeasures to unloading atrophy will require more research.

Non-NASA Center↗

NASA NTRS2001

Hindlimb unloading induces a collagen isoform shift in the soleus muscle of the rat

To determine whether hindlimb unloading (HU) alters the extracellular matrix of skeletal muscle, male Sprague-Dawley rats were subjected to 0 (n = 11), 1 (n = 11), 14 (n = 13), or 28 (n = 11) days of unloading. Remodeling of the soleus and plantaris muscles was examined biochemically for collagen abundance via measurement of hydroxyproline, and the percentage of cross-sectional area of collagen was determined histologically with picrosirius red staining. Total hydroxyproline content in the soleus and plantaris muscles was unaltered by HU at any time point. However, the relative proportions of type I collagen in the soleus muscle decreased relative to control (Con) with 14 and 28 days HU (Con 68 +/- 5%; 14 days HU 53 +/- 4%; 28 days HU 53 +/- 7%). Correspondingly, type III collagen increased in soleus muscle with 14 and 28 days HU (Con 32 +/- 5%; 14 days HU 47 +/- 4%; 28 days HU 48 +/- 7%). The proportion of type I muscle fibers in soleus muscle was diminished with HU (Con 96 +/- 2%; 14 days HU 86 +/- 1%; 28 days HU 83 +/- 1%), and the proportion of hybrid type I/IIB fibers increased (Con 0%; 14 days HU 8 +/- 2%; 28 days HU 14 +/- 2%). HU had no effect on the proportion of type I and III collagen or muscle fiber composition in plantaris muscle. The data demonstrate that HU induces a shift in the relative proportion of collagen isoform (type I to III) in the antigravity soleus muscle, which occurs concomitantly with a slow-to-fast myofiber transformation.

Non-NASA Center↗

NASA NTRS1999

Space travel directly induces skeletal muscle atrophy

Space travel causes rapid and pronounced skeletal muscle wasting in humans that reduces their long-term flight capabilities. To develop effective countermeasures, the basis of this atrophy needs to be better understood. Space travel may cause muscle atrophy indirectly by altering circulating levels of factors such as growth hormone, glucocorticoids, and anabolic steroids and/or by a direct effect on the muscle fibers themselves. To determine whether skeletal muscle cells are directly affected by space travel, tissue-cultured avian skeletal muscle cells were tissue engineered into bioartificial muscles and flown in perfusion bioreactors for 9 to 10 days aboard the Space Transportation System (STS, i.e., Space Shuttle). Significant muscle fiber atrophy occurred due to a decrease in protein synthesis rates without alterations in protein degradation. Return of the muscle cells to Earth stimulated protein synthesis rates of both muscle-specific and extracellular matrix proteins relative to ground controls. These results show for the first time that skeletal muscle fibers are directly responsive to space travel and should be a target for countermeasure development.

NASA Discipline Musculoskeletal↗

NASA NTRS1999

Macrophage invasion does not contribute to muscle membrane injury during inflammation

Previous observations have shown that neutrophil invasion precedes macrophage invasion during muscle inflammation and that peak muscle injury is observed at the peak of ED1+ macrophage invasion. We tested the hypothesis that neutrophil invasion causes subsequent invasion by ED1+ macrophages and that ED1+ macrophages then contribute significantly to muscle membrane injury during modified muscle use. Rat hindlimbs were unloaded for 10 days followed by reloading by normal ambulation to induce inflammation. Membrane injury was measured by assaying Evans blue-bound serum protein influx through membrane lesions. Muscle neutrophil populations increased significantly during the first 2 h of reloading but ED1+ macrophages did not increase until 24 h. Neutrophil invasion was uncoupled from subsequent macrophage invasion by reloading rat hindlimbs for 2 h to cause neutrophil invasion, followed by resuspension for hours 2-24. This produced similar increases in neutrophil concentration as measured in muscles continuously reloaded for 24 h without causing an increase in macrophages. However, resuspension did not reduce the extent of muscle damage compared with that occurring in muscles that were reloaded continuously for 24 h. Thus, muscle invasion by neutrophils is not sufficient to cause invasion by ED1+ macrophages. In addition, muscle membrane injury that occurs during reloading is independent of invasion by ED1+ macrophages.

NASA Discipline Musculoskeletal↗

NASA NTRS1998

Overexpression of IGF-I in skeletal muscle of transgenic mice does not prevent unloading-induced atrophy

This study examined the association between local insulin-like growth factor I (IGF-I) overexpression and atrophy in skeletal muscle. We hypothesized that endogenous skeletal muscle IGF-I mRNA expression would decrease with hindlimb unloading (HU) in mice, and that transgenic mice overexpressing human IGF-I (hIGF-I) specifically in skeletal muscle would exhibit less atrophy after HU. Male transgenic mice and nontransgenic mice from the parent strain (FVB) were divided into four groups (n = 10/group): 1) transgenic, weight-bearing (IGF-I/WB); 2) transgenic, hindlimb unloaded (IGF-I/HU); 3) nontransgenic, weight-bearing (FVB/WB); and 4) nontransgenic, hindlimb unloaded (FVB/HU). HU groups were hindlimb unloaded for 14 days. Body mass was reduced (P < 0.05) after HU in both IGF-I (-9%) and FVB mice (-13%). Contrary to our hypothesis, we found that the relative abundance of mRNA for the endogenous rodent IGF-I (rIGF-I) was unaltered by HU in the gastrocnemius (GAST) muscle of wild-type FVB mice. High-level expression of hIGF-I peptide and mRNA was confirmed in the GAST and tibialis anterior (TA) muscles of the transgenic mice. Nevertheless, masses of the GAST and TA muscles were reduced (P < 0.05) in both FVB/HU and IGF-I/HU groups compared with FVB/WB and IGF-I/WB groups, respectively, and the percent atrophy in mass of these muscles did not differ between FVB and IGF-I mice. Therefore, skeletal muscle atrophy may not be associated with a reduction of endogenous rIGF-I mRNA level in 14-day HU mice. We conclude that high local expression of hIGF-I mRNA and peptide in skeletal muscle alone cannot attenuate unloading-induced atrophy of fast-twitch muscle in mice.

NASA Discipline Musculoskeletal↗