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At least 253 records · Page 14
All sourcesNASA NTRSDOE OSTI
NASA NTRS1992

Exercise training, glucose transporters, and glucose transport in rat skeletal muscles

It was previously found that voluntary wheel running induces an increase in the insulin-sensitive glucose transporter, i.e., the GLUT4 isoform, in rat plantaris muscle (K. J. Rodnick, J. O. Holloszy, C. E. Mondon, and D. E. James. Diabetes 39: 1425-1429, 1990). The present study was undertaken to determine whether 1) the increase in muscle GLUT4 protein is associated with an increase in maximally stimulated glucose transport activity, 2) a conversion of type IIb to type IIa or type I muscle fibers plays a role in the increase in GLUT4 protein, and 3) an increase in the GLUT1 isoform is a component of the adaptation of muscle to endurance exercise. Five weeks of voluntary wheel running that resulted in a 33% increase in citrate synthase activity induced a 50% increase in GLUT4 protein in epitrochlearis muscles of female Sprague-Dawley rats. The rate of 2-deoxy-glucose transport maximally stimulated with insulin or insulin plus contractions was increased approximately 40% (P less than 0.05). There was no change in muscle fiber type composition, evaluated by myosin ATPase staining, in the epitrochlearis. There was also no change in GLUT1 protein concentration. We conclude that an increase in GLUT4, but not of GLUT1 protein, is a component of the adaptive response of muscle to endurance exercise and that the increase in GLUT4 protein is associated with an increased capacity for glucose transport.

NASA Discipline Cell Biology↗
NASA NTRS1990

Metabolic and morphologic properties of single muscle fibers in the rat after spaceflight, Cosmos 1887

The adaptation of a slow (soleus, Sol) and a fast (medial gastrocnemius, MG) skeletal muscle to spaceflight was studied in five young male rats. The flight period was 12.5 days and the rats were killed approximately 48 h after returning to 1 g. Five other rats that were housed in cages similar to those used by the flight rats were maintained at 1 g for the same period of time to serve as ground-based controls. Fibers were classified as dark or light staining for myosin adenosine triphosphatase (ATPase). On the average, the fibers in the Sol of the flight rats atrophied twice as much as those in the MG. Further, the fibers located in the deep (close to the bone and having the highest percentage of light ATPase and high oxidative fibers in the muscle cross section) region of the MG atrophied more than the fibers located in the superficial (away from the bone and having the lowest percentage of light ATPase and high oxidative fibers in the muscle cross-section) region of the muscle. Based on quantitative histochemical assays of single muscle fibers, succinate dehydrogenase (SDH) activity per unit volume was unchanged in fibers of the Sol and MG. However, in the Sol, but not the MG, the total amount of SDH activity in a 10-microns-thick section of a fiber decreased significantly in response to spaceflight. Based on population distributions, it appears that the alpha-glycerophosphate dehydrogenase (GPD) activities were elevated in the dark ATPase fibers in the Sol, whereas the light fibers in the Sol and both fiber types in the MG did not appear to change. The ratio of GPD to SDH activities increased in the dark (but not light) fibers of the Sol and was unaffected in the MG. Immunohistochemical analyses indicate that approximately 40% of the fibers in the Sol of flight rats expressed a fast myosin heavy chain compared with 22% in control rats. Further, 31% of the fibers in the Sol of flight rats expressed both fast and slow myosin heavy chains compared with 8% in control rats. Immunohistochemical changes in the MG were minimal. These data suggest that the magnitude and direction of enzymatic activity and cell volume changes are dependent on the muscle, the region of the muscle, and the type of myosin expressed in the fibers. Further, the ability of fibers to maintain normal or even elevated activities per unit volume of some metabolic enzymes is remarkable considering the marked and rapid decrease in fiber volume.

NASA Experiment Number COS 1887-26↗
NASA NTRS2008

Different Levels of Eccentric Resistance during Eight Weeks of Training Affect Muscle Strength and Lean Tissue Mass

Coupling concentric and eccentric muscle contractions appears to be important in the development of muscle strength and hypertrophy. The interim Resistive Exercise Device (iRED) currently used aboard the International Space Station does not seem to be as effective as free weight training in ambulatory subjects and has not completely protected against muscular deconditioning due to space flight. The lack of protection during space flight could be caused by iRED's proportionally lower eccentric resistance (60-70%) compared to concentric resistance. PURPOSE: To determine the effects of 8 wks of lower body resistive exercise training using five levels of eccentric resistance on muscle strength and lean tissue mass. METHODS: Forty untrained males (34.9 +/- 7 yrs, 80.9 +/- 9.8 kg, 178.2 +/- 7.1 cm; mean +/- SD) completed three 1-repetition maximum (1-RM) strength tests for both the supine leg press (LP) and supine heel raise (HR) prior to training; subjects were matched for LP strength and randomly assigned to one of five training groups. Concentric load (% 1-RM) was constant across groups during training, but each group trained with different levels of eccentric load (0%, 33%, 66%, 100%, or 138% of concentric). Subjects trained 3 d / wk for 8 wks using a periodized program for LP and HR based on percentages of the highest pre-training 1-RM. LP and HR 1-RM and leg lean mass (LLM; assessed by DEXA) were measured pre- and post-training. A two-way ANOVA was used to analyze all dependent measures. Tukey's post hoc tests were used to test significant main effects. Within group pre- to post-training changes were compared using paired t-tests with a Bonferroni adjustment. Statistical significance was set a priori at p 0.05. All data are expressed as mean +/- SE. RESULTS: LP 1-RM strength increased significantly in all groups pre- to post-training. The 138% group increase (20.1 +/- 3.7%) was significantly greater than the 0% (7.9 +/- 2.8%), 33% (7.7 +/- 4.6%), and 66% (7.5 +/- 4.3%) groups. All groups significantly increased HR strength pre- to posttraining (33%: 7.5 +/- 6.1%; 66%: 6.6 +/- 3.7%; 100%: 12.2 +/- 1.8%; 138%: 11.0 +/- 6.4%) except for the 0% (4.9 +/- 9.1%) group. There were no differences between groups. LLM increased significantly pre- to post-training in only the 138% group; there were no differences between groups. CONCLUSIONS: Eight wks of lower body resistive exercise training with eccentric overload resulted in greater increases in LP strength than training with eccentric loads of 66% or less. Post-training HR strength was not affected by eccentric training load, perhaps because of the predominance of Type I fibers typical in the gastrocnemius. Only 138% eccentric training significantly increased LLM. PRACTICAL APPLICATIONS: For athletes or others desiring to maximize muscle strength and hypertrophy gains, training with eccentric loads greater than 100% of concentric resistance will provide greater increases in muscle strength and lean tissue mass in some muscle groups. In a rehabilitation or geriatric exercise setting that places primary emphasis on program adherence and moderate strength gains, training with an eccentric underload may provide strength increases comparable to those of traditional 1:1 training but with less muscle soreness and physiologic insult to the patient, but this has yet to be proven.

English, K. L.↗
DOE OSTI2024

Cysteine Rich Intestinal Protein 2 is a copper-responsive regulator of skeletal muscle differentiation and metal homeostasis

Copper (Cu) is essential for respiration, neurotransmitter synthesis, oxidative stress response, and transcription regulation, with imbalances leading to neurological, cognitive, and muscular disorders. Here we show the role of a novel Cu-binding protein (Cu-BP) in mammalian transcriptional regulation, specifically on skeletal muscle differentiation using murine primary myoblasts. Utilizing synchrotron X-ray fluorescence-mass spectrometry, we identified murine cysteine-rich intestinal protein 2 (mCrip2) as a key Cu-BP abundant in both nuclear and cytosolic fractions. mCrip2 binds two to four Cu + ions with high affinity and presents limited redox potential. CRISPR/Cas9-mediated deletion of mCrip2 impaired myogenesis, likely due to Cu accumulation in cells. CUT&RUN and transcriptome analyses revealed its association with gene promoters, including MyoD1 and metallothioneins, suggesting a novel Cu-responsive regulatory role for mCrip2. Our work describes the significance of mCrip2 in skeletal muscle differentiation and metal homeostasis, expanding understanding of the Cu-network in myoblasts. Copper (Cu) is essential for various cellular processes, including respiration and stress response, but imbalances can cause serious health issues. This study reveals a new Cu-binding protein (Cu-BP) involved in muscle development in primary myoblasts. Using unbiased metalloproteomic techniques and high throughput sequencing, we identified mCrip2 as a key Cu-BP found in cell nuclei and cytoplasm. mCrip2 binds up to four Cu + ions and has a limited redox potential. Deleting mCrip2 using CRISPR/Cas9 disrupted muscle formation due to Cu accumulation. Further analyses showed that mCrip2 regulates the expression of genes like MyoD1, essential for muscle differentiation, and metallothioneins in response to copper supplementation. This research highlights the importance of mCrip2 in muscle development and metal homeostasis, providing new insights into the Cu-network in cells.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS2003

Hypercortisolemia alters muscle protein anabolism following ingestion of essential amino acids

Debilitating injury is accompanied by hypercortisolemia, muscle wasting, and disruption of the normal anabolic response to food. We sought to determine whether acute hypercortisolemia alters muscle protein metabolism following ingestion of a potent anabolic stimulus: essential amino acids (EAA). A 27-h infusion (80 microg. kg(-1). h(-1)) of hydrocortisone sodium succinate mimicked cortisol (C) levels accompanying severe injury (>30 microg/dl), (C + AA; n = 6). The control group (AA) received intravenous saline (n = 6). Femoral arteriovenous blood samples and muscle biopsies were obtained during a primed (2.0 micromol/kg) constant infusion (0.05 micromol. kg(-1). min(-1)) of l-[ring-(2)H(5)]phenylalanine before and after ingestion of 15 g of EAA. Hypercortisolemia [36.5 +/- 2.1 (C + AA) vs. 9.0 +/- 1.0 microg/dl (AA)] increased postabsorptive arterial, venous, and muscle intracellular phenylalanine concentrations. Hypercortisolemia also increased postabsorptive and post-EAA insulin concentrations. Net protein balance was blunted (40% lower) following EAA ingestion but remained positive for a greater period of time (60 vs. 180 min) in the C + AA group. Thus, although differences in protein metabolism were evident, EAA ingestion improved muscle protein anabolism during acute hypercortisolemia and may help minimize muscle loss following debilitating injury.

Clinical Trial↗
NASA NTRS1997

Insulin attenuates atrophy of unweighted soleus muscle by amplified inhibition of protein degradation

Unweighting atrophy of immature soleus muscle occurs rapidly over the first several days, followed by slower atrophy coinciding with increased sensitivity to insulin of in vitro protein metabolism. This study determined whether this increased sensitivity might account for the diminution of atrophy after 3 days of tall-cast hindlimb suspension. The physiological significance of the increased response to insulin in unweighted muscle was evaluated by analyzing in vivo protein metabolism for day 3 (48 to 72 hours) and day 4 (72 to 96 hours) of unweighting in diabetic animals either injected with insulin or not treated. Soleus from nontreated diabetic animals showed a similar loss of protein during day 3 (-16.2%) and day 4 (-14.5%) of unweighting, whereas muscle from insulin-treated animals showed rapid atrophy (-14.5%) during day 3 only, declining to just -3.1% the next day. Since fractional protein synthesis was similar for both day 3 (8.6%/d) and day 4 (7.0%/d) of unweighting in insulin-treated animals, the reduction in protein loss must be accounted for by a slowing of protein degradation due to circulating insulin. Intramuscular (IM) injection of insulin (600 nmol/L) stimulated in situ protein synthesis similarly in 4-day unweighted (+56%) and weight-bearing (+90%) soleus, even though unweighted muscle showed a greater in situ response of 2-deoxy-[3H]glucose uptake to IM injection of either insulin (133 nmol/L) or insulin-like growth factor-I (IGF-I) (200 nmol/L) than control muscle. These findings suggest that unweighted muscle is selectively more responsive in vivo to insulin, and that the slower atrophy after 3 days of unweighting was due to an increased effect of insulin on inhibiting protein degradation.

NASA Discipline Musculoskeletal↗
NASA NTRS1996

Effect of spaceflight on the functional, biochemical, and metabolic properties of skeletal muscle

This paper summarizes the effects of spaceflight on the functional, morphological, and biochemical properties of human and rodent skeletal muscle. The findings suggest that following as little as 5-6 in space there are deficits in both human and rodent motor capacity, strength, and endurance properties of skeletal muscle. The reduced strength is associated, in part, with a reduction in muscle mass as reflected in smaller cross-sectional areas of both fast- and slow-twitch fibers. Available evidence in animal models suggests that slow-twitch fibers are more sensitive to the atrophying process. Accompanying the atrophy is a transformation of slow to fast protein phenotype involving myosin heavy chain and sarcoplasmic reticulum protein isoforms. These transformations appear to be regulated, in part, by pretranslational processes. Data on the oxidative capacity of rodent skeletal muscle suggest a bias toward preferential utilization of carbohydrate as the primary substrate. These collective findings suggest that skeletal muscles comprised chiefly of slow fibers are highly dependent on gravity for the normal expression of protein mass and slow phenotype. Future studies need to focus on elucidating the mechanisms associated with the atrophy response, as well as identifying suitable exercise and other countermeasures capable of preserving the structural and functional integrity of skeletal muscle.

NASA Discipline Musculoskeletal↗
NASA NTRS1995

Changes in diaphragm muscle collagen gene expression after acute unilateral denervation

The purpose of the present study was to examine the effects of acute (3 days) unilateral diaphragm denervation (DNV) on 1) levels of alpha 1(I) and alpha 1(III) procollagen mRNA; 2) collagen concentration [hydroxyproline (HYP)]; 3) amount of the nonreducible collagen cross-link hydroxylysylpyridinoline (HP); and 4) the passive force-length relationship of the muscle. The levels of alpha 1(I) and alpha 1(III) procollagen mRNA, HYP concentration, and amount of HP were measured in muscle segments from the midcostal region of DNV and intact (INT) hemidiaphragms of adult male Fischer 344 rats (250-300 g). The in vitro passive force-length relationship of DNV and INT hemidiaphragm was determined by lengthening and shortening the diaphragm muscle segments from 85 to 115% of optimal length at a constant velocity (0.6 optimal length/s). Three days after DNV, the level of alpha 1(I) procollagen mRNA was increased over 15-fold in the DNV hemidiaphragm compared with INT (P < 0.05), whereas the level of alpha 1(III) procollagen mRNA was increased by approximately sixfold in the DNV hemidiaphragm compared with INT (P < 0.05). Collagen (HYP) concentration did not differ between groups, averaging 8.7 and 8.9 micrograms/mg dry wt for the DNV and INT hemidiaphragms, respectively. In addition, there was no difference in the amount of the mature nonreducible collagen cross-link HP between the DNV and INT hemidiaphragms (0.66 vs. 0.76 mole HP/mole collagen, respectively). The amount of passive force developed during lengthening did not differ between DNV and INT hemidiaphragms. These data indicate that acute DNV of the hemidiaphragm is associated with an increase in the mRNA level of the two principal fibrillar collagen phenotypes in skeletal muscle. However, despite extensive muscle remodeling, the passive force-length relationship of the DNV hemidiaphragm is unaffected compared with the INT muscle.

Non-NASA Center↗
DOE OSTI2016

TGF-β1 activates the canonical NF-κB signaling to promote cell survival and proliferation in dystrophic muscle fibroblasts in vitro

Activated fibroblasts continue to proliferate at injury sites, leading to progressive muscular fibrosis in Duchenne muscular dystrophy (DMD). TGF-β1 is a dominant profibrotic mediator thought to play a critical role in muscle fibrosis; however, the implicated mechanisms are not fully understood. Here we showed that TGF-β1 increased the resistance to apoptosis and stimulated cell cycle progression in dystrophic muscle fibroblasts under serum deprivation conditions in vitro. TGF-β1 treatment activated the canonical NF-κB pathway; and we found that pharmacological inhibition of IKKβ with IMD-0354 and RelA gene knockdown with siRNA attenuated these effects of TGF-β1 on dystrophic muscle fibroblasts. Collectively, our data suggest that TGF-β1 prevents apoptosis and cell cycle arrest in dystrophic muscle fibroblasts through the canonical NF-κB signaling pathway. - Highlights: • TGF-β1 promotes survival and proliferation in dystrophic muscle fibroblasts. • TGF-β1 activated the canonical NF-κB pathway in dystrophic muscle fibroblasts. • Canonical NF-κB pathway mediates these effects of TGF-β1.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

Effect of a high dose of simvastatin on muscle mitochondrial metabolism and calcium signaling in healthy volunteers

Statin use may be limited by muscle side effects. Although incompletely understood to date, their pathophysiology may involve oxidative stress and impairments of mitochondrial function and of muscle Ca{sup 2+} homeostasis. In order to simultaneously assess these mechanisms, 24 male healthy volunteers were randomized to receive either simvastatin for 80 mg daily or placebo for 8 weeks. Blood and urine samples and a stress test were performed at baseline and at follow-up, and mitochondrial respiration and Ca{sup 2+} spark properties were evaluated on a muscle biopsy 4 days before the second stress test. Simvastatin-treated subjects were separated according to their median creatine kinase (CK) increase. Simvastatin treatment induced a significant elevation of aspartate amino transferase (3.38 ± 5.68 vs − 1.15 ± 4.32 UI/L, P < 0.001) and CK (− 24.3 ± 99.1 ± 189.3vs 48.3 UI/L, P = 0.01) and a trend to an elevation of isoprostanes (193 ± 408 vs12 ± 53 pmol/mmol creatinine, P = 0.09) with no global change in mitochondrial respiration, lactate/pyruvate ratio or Ca{sup 2+} sparks. However, among statin-treated subjects, those with the highest CK increase displayed a significantly lower Vmax rotenone succinate and an increase in Ca{sup 2+} spark amplitude vs both subjects with the lowest CK increase and placebo-treated subjects. Moreover, Ca{sup 2+} spark amplitude was positively correlated with treatment-induced CK increase in the whole group (r = 0.71, P = 0.0045). In conclusion, this study further supports that statin induced muscular toxicity may be related to alterations in mitochondrial respiration and muscle calcium homeostasis independently of underlying disease or concomitant medication. -- Highlights: ► Statin use may be limited by side effects, particularly myopathy. ► Statins might impair mitochondrial function and muscle Ca2+ signaling in muscle. ► This was tested among healthy volunteers receiving simvastatin 80 mg daily for 8 weeks. ► CK increase was associated with alterations in Ca2+ sparks and mitochondrial function.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2012

The non-competitive acetylcholinesterase inhibitor APS12-2 is a potent antagonist of skeletal muscle nicotinic acetylcholine receptors

APS12-2, a non-competitive acetylcholinesterase inhibitor, is one of the synthetic analogs of polymeric alkylpyridinium salts (poly-APS) isolated from the marine sponge Reniera sarai. In the present work the effects of APS12-2 were studied on isolated mouse phrenic nerve–hemidiaphragm muscle preparations, using twitch tension measurements and electrophysiological recordings. APS12-2 in a concentration-dependent manner blocked nerve-evoked isometric muscle contraction (IC{sub 50} = 0.74 μM), without affecting directly-elicited twitch tension up to 2.72 μM. The compound (0.007–3.40 μM) decreased the amplitude of miniature endplate potentials until a complete block by concentrations higher than 0.68 μM, without affecting their frequency. Full size endplate potentials, recorded after blocking voltage-gated muscle sodium channels, were inhibited by APS12-2 in a concentration-dependent manner (IC{sub 50} = 0.36 μM) without significant change in the resting membrane potential of the muscle fibers up to 3.40 μM. The compound also blocked acetylcholine-evoked inward currents in Xenopus oocytes in which Torpedo (α1{sub 2}β1γδ) muscle-type nicotinic acetylcholine receptors (nAChRs) have been incorporated (IC{sub 50} = 0.0005 μM), indicating a higher affinity of the compound for Torpedo (α1{sub 2}β1γδ) than for the mouse (α1{sub 2}β1γε) nAChR. Our data show for the first time that APS12-2 blocks neuromuscular transmission by a non-depolarizing mechanism through an action on postsynaptic nAChRs of the skeletal neuromuscular junction. -- Highlights: ► APS12-2 produces concentration-dependent inhibition of nerve-evoked muscle contraction in vitro. ► APS12-2 blocks MEPPs and EPPs at the neuromuscular junction. APS12-2 blocks ACh-activated current in Xenopus oocytes incorporated with Torpedo nAChRs.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Defining the role of mesenchymal stromal cells on the regulation of matrix metalloproteinases in skeletal muscle cells

Recent studies indicate that mesenchymal stromal cell (MSC) transplantation improves healing of injured and diseased skeletal muscle, although the mechanisms of benefit are poorly understood. In the present study, we investigated whether MSCs and/or their trophic factors were able to regulate matrix metalloproteinase (MMP) expression and activity in different cells of the muscle tissue. MSCs in co-culture with C2C12 cells or their conditioned medium (MSC-CM) up-regulated MMP-2 and MMP-9 expression and function in the myoblastic cells; these effects were concomitant with the down-regulation of the tissue inhibitor of metalloproteinases (TIMP)-1 and -2 and with increased cell motility. In the single muscle fiber experiments, MSC-CM administration increased MMP-2/9 expression in Pax-7{sup +} satellite cells and stimulated their mobilization, differentiation and fusion. The anti-fibrotic properties of MSC-CM involved also the regulation of MMPs by skeletal fibroblasts and the inhibition of their differentiation into myofibroblasts. The treatment with SB-3CT, a potent MMP inhibitor, prevented in these cells, the decrease of α-smooth actin and type-I collagen expression induced by MSC-CM, suggesting that MSC-CM could attenuate the fibrogenic response through mechanisms mediated by MMPs. Our results indicate that growth factors and cytokines released by these cells may modulate the fibrotic response and improve the endogenous mechanisms of muscle repair/regeneration. - Highlights: • MSC-CM contains paracrine factors that up-regulate MMP expression and function in different skeletal muscle cells. • MSC-CM promotes myoblast and satellite cell migration, proliferation and differentiation. • MSC-CM negatively interferes with fibroblast-myoblast transition in primary skeletal fibroblasts. • Paracrine factors from MSCs modulate the fibrotic response and improve the endogenous mechanisms of muscle regeneration.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

An oscillatory network controlling self-renewal of skeletal muscle stem cells

The balance between proliferation and differentiation of muscle stem cells is tightly controlled, ensuring the maintenance of a cellular pool needed for muscle growth and repair. Muscle stem cells can proliferate, they can generate differentiating cells, or they self-renew to produce new stem cells. Notch signaling plays a crucial role in this process. Recent studies revealed that expression of the Notch effector HES1 oscillates in activated muscle stem cells. The oscillatory expression of HES1 periodically represses transcription from the genes encoding the myogenic transcription factor MYOD and the Notch ligand DLL1, thereby driving MYOD and DLL1 oscillations. This oscillatory network allows muscle progenitor cells and activated muscle stem cells to remain in a proliferative and ‘undecided’ state, in which they can either differentiate or self-renew. When HES1 is downregulated, MYOD oscillations become unstable and are replaced by sustained expression, which drives the cells into terminal differentiation. During development and regeneration, proliferating stem cells contact each other and the stability of the oscillatory expression depends on regular DLL1 inputs provided by neighboring cells. In such communities of cells that receive and provide Notch signals, the appropriate timing of DLL1 inputs is important, as sustained DLL1 cannot replace oscillatory DLL1. Thus, in cell communities, DLL1 oscillations ensure the appropriate balance between self-renewal and differentiation. In summary, oscillations in myogenic cells are an important example of dynamic gene expression determining cell fate.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2025

Markers of mitochondrial function and oxidative metabolism in skeletal muscle do not display intrinsic circadian regulation in female mice

Mitochondria are key regulators of metabolism and ATP supply in skeletal muscle, while circadian rhythms influence many physiological processes. However, whether mitochondrial function is intrinsically regulated in a circadian manner in mouse skeletal muscle is inadequately understood. Accordingly, we measured postabsorptive transcript abundance of markers of mitochondrial autophagy, dynamics, and metabolism [extensor digitorum longus (EDL), soleus, gastrocnemius], protein abundance of electron transport chain complexes (EDL and soleus), enzymatic activity of succinate dehydrogenase (tibialis anterior and plantaris), and maximal mitochondrial respiration (tibialis anterior) in different skeletal muscles from female C57BL/6NJ mice at four zeitgeber times: 1, 7, 13, and 19. Our findings demonstrate that markers of mitochondrial function and oxidative metabolism do not display intrinsic time-of-day regulation at the gene, protein, enzymatic, or functional level. The core-clock genes Bmal1 and Dbp exhibited intrinsic circadian rhythmicity in skeletal muscle (i.e., EDL, soleus, gastrocnemius) and circadian amplitude varied by muscle type. These findings demonstrate that female mouse skeletal muscle does not display circadian regulation of markers of mitochondrial function or oxidative metabolism over 24 h.

Circadian Biology↗
DOE OSTI2019

Experimental Preservation of Muscle Tissue in Quartz Sand and Kaolinite

Siliciclastic sediments of the Ediacaran Period contain exceptionally preserved fossils of macroscopic organisms, including three-dimensional casts and molds commonly found in sandstones and siltstones and some two-dimensional compressions reported in shales. The sporadic and variable associations of these exceptionally preserved macroscopic fossils with pyrite, clay minerals, and microbial fossils and textures complicate our understanding of fossilization processes. This hinders inferences about the evolutionary histories, tissue types, original morphologies, and lifestyles of the enigmatic Ediacara biota. In this work, we investigate the delayed decay of scallop muscles buried in quartz sand or kaolinite for 45 days. This process occurs in the presence of microbial activity in mixed redox environments, but in the absence of thick, sealing microbial mats. Furthermore, microbial processes that mediate organic decay and release the highest concentrations of silica and Fe(II) into the pore fluids are associated with the most extensive tissue decay. Delayed decay and the preservation of thick muscles in sand are associated with less intense microbial iron reduction and the precipitation of iron oxides and iron sulfides that contain Fe(II) or Fe(III). In contrast, muscles buried in kaolinite are coated only by <10 μm-thick clay veneers composed of kaolinite grains and newly formed K- and Fe(II)-rich aluminosilicate phases. Muscles that undergo delayed decay in kaolinite lose more mass relative to the muscles buried in sand and undergo vertical collapse. These findings show that the composition of minerals that coat or precipitate within the tissues and the vertical dimension of the preserved features can depend on the type of sediment that buries the muscles. Similar processes in the zone of oscillating redox likely facilitated the formation of exceptionally preserved macrofossils in Ediacaran siliciclastic sediments.

58 GEOSCIENCES↗
NASA NTRS2003

TNF-alpha increases ubiquitin-conjugating activity in skeletal muscle by up-regulating UbcH2/E220k

In some inflammatory diseases, TNF-alpha is thought to stimulate muscle catabolism via an NF-kappaB-dependent process that increases ubiquitin conjugation to muscle proteins. The transcriptional mechanism of this response has not been determined. Here we studied the potential role of UbcH2, a ubiquitin carrier protein and homologue of murine E220k. We find that UbcH2 is constitutively expressed by human skeletal and cardiac muscles, murine limb muscle, and cultured myotubes. TNF-alpha stimulates UbcH2 expression in mouse limb muscles in vivo and in cultured myotubes. The UbcH2 promoter region contains a functional NF-kappaB binding site; NF-kappaB binding to this sequence is increased by TNF-alpha stimulation. A dominant negative inhibitor of NF-kappaB activation blocks both UbcH2 up-regulation and the increase in ubiquitin-conjugating activity stimulated by TNF-alpha. In extracts from TNF-alpha-treated myotubes, ubiquitin-conjugating activity is limited by UbcH2 availability; activity is inhibited by an antiserum to UbcH2 or a dominant negative mutant of UbcH2 and is enhanced by wild-type UbcH2. Thus, UbcH2 up-regulation is a novel response to TNF-alpha/NF-kappaB signaling in skeletal muscle that appears to be essential for the increased ubiquitin conjugation induced by this cytokine.

Non-NASA Center↗
NASA NTRS2002

Effects of microgravity on myogenic factor expressions during postnatal development of rat skeletal muscle

To clarify the role of gravity in the postnatal development of skeletal muscle, we exposed neonatal rats at 7 days of age to microgravity. After 16 days of spaceflight, tibialis anterior, plantaris, medial gastrocnemius, and soleus muscles were removed from the hindlimb musculature and examined for the expression of MyoD-family transcription factors such as MyoD, myogenin, and MRF4. For this purpose, we established a unique semiquantitative method, based on RT-PCR, using specific primers tagged with infrared fluorescence. The relative expression of MyoD in the tibialis anterior and plantaris muscles and that of myogenin in the plantaris and soleus muscles were significantly reduced (P < 0.001) in the flight animals. In contrast, MRF4 expression was not changed in any muscle. These results suggest that MyoD and myogenin, but not MRF4, are sensitive to gravity-related stimuli in some skeletal muscles during postnatal development.

Non-NASA Center↗
NASA NTRS2001

The molecular responses of skeletal muscle satellite cells to continuous expression of IGF-1: implications for the rescue of induced muscular atrophy in aged rats

Approximately 50% of humans older than 85 years have physical frailty due to weak skeletal muscles. This indicates a need for determining mechanisms to combat this problem. A critical cellular factor for postnatal muscle growth is a population of myogenic precursor cells called satellite cells. Given the complex process of sarcopenia, it has been postulated that, at some point in this process, a limited satellite cell proliferation potential could become rate-limiting to the regrowth of old muscles. It is conceivable that if satellite cell proliferative capacity can be maintained or enhanced with advanced age, sarcopenia could potentially be delayed or prevented. Therefore, the purposes of this paper are to describe whether IGF-I can prevent muscular atrophy induced by repeated cycles of hindlimb immobilization, increase the in vitro proliferation in satellite cells from these muscles and, if so, the molecular mechanisms by which IGF-I mediates this increased proliferation. Our results provide evidence that IGF-I can enhance aged muscle regrowth possibly through increased satellite cell proliferation. The results also suggest that IGF-I enhances satellite cell proliferation by decreasing the cell cycle inhibitor, p27Kip1, through the PI3'-K/Akt pathway. These data provide molecular evidence for IGF-I's rescue effect upon aging-associated skeletal muscle atrophy.

NASA Discipline Musculoskeletal↗