Functional and anatomical variations in retinorecipient brain areas in Arvicanthis niloticus and Rattus norvegicus: implications for the circadian and masking systems.

Daily rhythms in light exposure influence the expression of behavior by entraining circadian rhythms and through its acute effects on behavior (i.e., masking). Importantly, these effects of light are dependent on the temporal niche of the organism; for diurnal organisms, light increases activity, whereas for nocturnal organisms, the opposite is true. Here we examined the functional and morphological differences between diurnal and nocturnal rodents in retinorecipient brain regions using Nile grass rats (Arvicanthis niloticus) and Sprague-Dawley (SD) rats (Rattus norvegicus), respectively. We established the presence of circadian rhythmicity in cFOS activation in retinorecipient brain regions in nocturnal and diurnal rodents housed in constant dark conditions to highlight different patterns between the temporal niches. We then assessed masking effects by comparing cFOS activation in constant darkness (DD) to that in a 12:12 light/dark (LD) cycle, confirming light responsiveness of these regions during times when masking occurs in nature. The intergeniculate leaflet (IGL) and olivary pretectal nucleus (OPN) exhibited significant variation among time points in DD of both species, but their expression profiles were not identical, as SD rats had very low expression levels for most timepoints. Light presentation in LD conditions induced clear rhythms in the IGL of SD rats but eliminated them in grass rats. Additionally, grass rats were the only species to demonstrate daily rhythms in LD for the habenula and showed a strong response to light in the superior colliculus. Structurally, we also analyzed the volumes of the visual brain regions using anatomical MRI, and we observed a significant increase in the relative size of several visual regions within diurnal grass rats, including the lateral geniculate nucleus, superior colliculus, and optic tract. Altogether, our results suggest that diurnal grass rats devote greater proportions of brain volume to visual regions than nocturnal rodents, and cFOS activation in these brain regions is dependent on temporal niche and lighting conditions.

Obesity and inactivity, not hyperglycemia, cause exercise intolerance in individuals with type 2 diabetes: Solving the obesity and inactivity versus hyperglycemia causality dilemma.

Obesity, a sedentary lifestyle and type 2 diabetes are intricately linked conditions contributing to reduced exercise tolerance, significant morbidity, and premature deaths. It is unknown whether the reported exercise intolerance associated with type 2 diabetes is a direct result of the hyperglycemia, the impact of a relatively sedentary lifestyle, or increased adiposity. We hypothesize that obesity and inactivity, not hyperglycemia, cause exercise intolerance in individuals with type 2 diabetes. An analysis of the literature and results from the Goto-Kakizaki (GK) rat model of type 2 diabetes strongly support this hypothesis. GK rats were not sedentary or obese when compared with Wistar control rats and did not have exercise intolerance. Specifically, despite being hyperglycemic, GK rats demonstrated a longer treadmill run time to exhaustion (150.6 ±â€¯9.0 vs. 77.2 ±â€¯12.9 min), further distance run (1506 ±â€¯90 vs. 772 ±â€¯129 m), more work performed per gram muscle (44.0 ±â€¯2.8 vs. 21.9 ±â€¯3.8 kg*m/g) and a small increase in total vertical work performed when accounting for body mass (116.8 ±â€¯6.3 versus 98.9 ±â€¯15.2 kg*m). These results document preserved exercise tolerance in the non-obese, non-sedentary GK rat supporting the hypothesis that the reported exercise intolerance in models of type 2 diabetes is dependent on obesity and inactivity. Solving the obesity and inactivity versus hyperglycemia causality dilemma is important in understanding the development of type 2 diabetes and implications for future pharmacological and life style interventions.

Effects of Nanoprobe Morphology on Cellular Binding and Inflammatory Responses: Hyaluronan-Conjugated Magnetic Nanoworms for Magnetic Resonance Imaging of Atherosclerotic Plaques.

Atherosclerosis is an inflammatory disease of arterial walls and the rupturing of atherosclerotic plaques is a major cause of heart attack and stroke. Imaging techniques that can enable the detection of atherosclerotic plaques before clinical manifestation are urgently needed. Magnetic resonance imaging (MRI) is a powerful technique to image the morphology of atherosclerotic plaques. In order to better analyze molecular processes in plaques, contrast agents that can selectively bind to plaque receptors will prove invaluable. CD44 is a cell surface protein overexpressed in plaque tissues, the level of which can be correlated with the risks of plaque rupture. Thus, targeting CD44 is an attractive strategy for detection of atherosclerotic plaques. Herein, we report the synthesis of hyaluronan-conjugated iron oxide nanoworms (HA-NWs). A new purification and gel electrophoresis protocol was developed to ensure the complete removal of free HA from HA-NWs. Compared to the more traditional spherical HA-bearing nanoparticles, HA-NWs had an elongated shape, which interacted much stronger with CD44-expressing cells in CD44- and HA-dependent manners. Furthermore, the HA-NWs did not induce much inflammatory response compared to the spherical HA nanoparticles. When assessed in vivo, HA-NWs enabled successful imaging of atherosclerotic plaques in a clinically relevant model of ApoE knockout transgenic mice for noninvasive plaque detection by MRI. Thus, nanoprobe shape engineering can be a useful strategy to significantly enhance their desired biological properties.

Chronic, complete cervical6-7 cord transection: distinct autonomic and cardiac deficits.

Spinal cord injury (SCI) resulting in tetraplegia is a devastating, life-changing insult causing paralysis and sensory impairment as well as distinct autonomic dysfunction that triggers compromised cardiovascular, bowel, bladder, and sexual activity. Life becomes a battle for independence as even routine bodily functions and the smallest activity of daily living become major challenges. Accordingly, there is a critical need for a chronic preclinical model of tetraplegia. This report addresses this critical need by comparing, for the first time, resting-, reflex-, and stress-induced cardiovascular, autonomic, and hormonal responses each week for 4 wk in 12 sham-operated intact rats and 12 rats with chronic, complete C6-7 spinal cord transection. Loss of supraspinal control to all sympathetic preganglionic neurons projecting to the heart and vasculature resulted in a profound bradycardia and hypotension, reduced cardiac sympathetic and parasympathetic tonus, reduced reflex- and stress-induced sympathetic responses, and reduced sympathetic support of blood pressure as well as enhanced reliance on angiotensin to maintain arterial blood pressure. Histological examination of the nucleus ambiguus and stellate ganglia supports the profound and distinct autonomic and cardiac deficits and reliance on angiotensin to maintain cardiovascular stability following chronic, complete cervical6-7 cord transection. NEW & NOTEWORTHY For the first time, resting-, reflex-, and stress-induced cardiovascular, autonomic, and hormonal responses were studied in rats with chronic, complete C6-7 cord transection. Loss of supraspinal control of all sympathetic preganglionic neurons reduced cardiac sympathetic and parasympathetic tonus, reflex and stress-induced sympathetic responses, and sympathetic support of blood pressure as well as enhanced reliance on angiotensin to maintain arterial blood pressure. Histological examination supports the distinct deficits associated with cervical cord injury.

Age Reduces Microvascular Function in the Leg Independent of Physical Activity.

The microvasculature is critical in the control of blood flow. Aging and reduced physical activity (PA) may both decrease microvascular function. PURPOSE: The primary aim was to evaluate the influence of age on microvascular function in adults with similar PA levels. Secondary aims were to assess the reliability of muscle functional magnetic resonance imaging in older adults (OA) and the relationship between PA and microvascular function in OA. METHODS: Microvascular blood-oxygen-level dependent (BOLD) responses were measured in young adults (YA, n = 12, mean ± SD age = 21 ± 1 yr old, PA = 239 ± 73 × 10 counts per day) and OA (n = 13, 64 ± 4 yr old, PA = 203 ± 48 × 10 counts per day). Functional magnetic resonance images (3T, echo planar BOLD) of the leg were acquired after brief (1 s) maximal voluntary isometric contractions. The test-retest reliability of BOLD responses and the Pearson correlation between peak BOLD and PA were assessed in a group of OA (OA-r) with a broad range of PA (66 ± 5 yr old, n = 9, PA range = 54 × 10 to 674 × 10 counts per day). RESULTS: Peak BOLD microvascular responses were reduced for OA compared with YA. OA peak BOLD was 27% lower in the soleus (3.3% ± 0.8% OA vs 4.5% ± 1.4% YA; P = 0.017) and 40% lower in the anterior compartment (1.6% ± 0.6% OA vs 2.7% ± 1.1% YA; P = 0.006). Coefficients of variation were 8.6% and 11.8% for peak BOLD in the soleus and anterior compartment, respectively, with an intraclass correlation of 0.950 for both muscle regions. The correlation between peak BOLD and PA was r ≥ 0.715, P ≤ 0.030. CONCLUSIONS: Aging was associated with reduced microvascular function in leg muscles, independent of PA. The findings also revealed good reliability for BOLD magnetic resonance imaging in OA for the soleus and anterior compartment muscles.

Multi-atlas-based fully automatic segmentation of individual muscles in rat leg.

OBJECTIVE: To quantify individual muscle volume in rat leg MR images using a fully automatic multi-atlas-based segmentation method. MATERIALS AND METHODS: We optimized a multi-atlas-based segmentation method to take into account the voxel anisotropy of numbers of MRI acquisition protocols. We mainly tested an image upsampling process along Z and a constraint on the nonlinear deformation in the XY plane. We also evaluated a weighted vote procedure and an original implementation of an artificial atlas addition. Using this approach, we measured gastrocnemius and plantaris muscle volumes and compared the results with manual segmentation. The method reliability for volume quantification was evaluated using the relative overlap index. RESULTS: The most accurate segmentation was obtained using a nonlinear registration constrained in the XY plane by zeroing the Z component of the displacement and a weighted vote procedure for both muscles regardless of the number of atlases. The performance of the automatic segmentation and the corresponding volume quantification outperformed the interoperator variability using a minimum of three original atlases. CONCLUSION: We demonstrated the reliability of a multi-atlas segmentation approach for the automatic segmentation and volume quantification of individual muscles in rat leg and found that constraining the registration in plane significantly improved the results.

Capsiate supplementation reduces oxidative cost of contraction in exercising mouse skeletal muscle in vivo.

Chronic administration of capsiate is known to accelerate whole-body basal energy metabolism, but the consequences in exercising skeletal muscle remain very poorly documented. In order to clarify this issue, the effect of 2-week daily administration of either vehicle (control) or purified capsiate (at 10- or 100-mg/kg body weight) on skeletal muscle function and energetics were investigated throughout a multidisciplinary approach combining in vivo and in vitro measurements in mice. Mechanical performance and energy metabolism were assessed strictly non-invasively in contracting gastrocnemius muscle using magnetic resonance (MR) imaging and 31-phosphorus MR spectroscopy (31P-MRS). Regardless of the dose, capsiate treatments markedly disturbed basal bioenergetics in vivo including intracellular pH alkalosis and decreased phosphocreatine content. Besides, capsiate administration did affect neither mitochondrial uncoupling protein-3 gene expression nor both basal and maximal oxygen consumption in isolated saponin-permeabilized fibers, but decreased by about twofold the Km of mitochondrial respiration for ADP. During a standardized in vivo fatiguing protocol (6-min of repeated maximal isometric contractions electrically induced at a frequency of 1.7 Hz), both capsiate treatments reduced oxidative cost of contraction by 30-40%, whereas force-generating capacity and fatigability were not changed. Moreover, the rate of phosphocreatine resynthesis during the post-electrostimulation recovery period remained unaffected by capsiate. Both capsiate treatments further promoted muscle mass gain, and the higher dose also reduced body weight gain and abdominal fat content. These findings demonstrate that, in addition to its anti-obesity effect, capsiate supplementation improves oxidative metabolism in exercising muscle, which strengthen this compound as a natural compound for improving health.

Human skeletal muscle metabolic economy in vivo: effects of contraction intensity, age, and mobility impairment.

We tested the hypothesis that older muscle has greater metabolic economy (ME) in vivo than young, in a manner dependent, in part, on contraction intensity. Twenty young (Y; 24±1 yr, 10 women), 18 older healthy (O; 73±2, 9 women) and 9 older individuals with mild-to-moderate mobility impairment (OI; 74±1, 7 women) received stimulated twitches (2 Hz, 3 min) and performed nonfatiguing voluntary (20, 50, and 100% maximal; 12 s each) isometric dorsiflexion contractions. Torque-time integrals (TTI; Nm·s) were calculated and expressed relative to maximal fat-free muscle cross-sectional area (cm2), and torque variability during voluntary contractions was calculated as the coefficient of variation. Total ATP cost of contraction (mM) was determined from flux through the creatine kinase reaction, nonoxidative glycolysis and oxidative phosphorylation, and used to calculate ME (Nm·s·cm(-2)·mM ATP(-1)). While twitch torque relaxation was slower in O and OI compared with Y (P≤0.001), twitch TTI, ATP cost, and economy were similar across groups (P≥0.15), indicating comparable intrinsic muscle economy during electrically induced isometric contractions in vivo. During voluntary contractions, normalized TTI and total ATP cost did not differ significantly across groups (P≥0.20). However, ME was lower in OI than Y or O at 20% and 50% MVC (P≤0.02), and torque variability was greater in OI than Y or O at 20% MVC (P≤0.05). These results refute the hypothesis of greater muscle ME in old age, and provide support for lower ME in impaired older adults as a potential mechanism or consequence of age-related reductions in functional mobility.

A single intake of capsiate improves mechanical performance and bioenergetics efficiency in contracting mouse skeletal muscle.

Capsiate is known to increase whole body oxygen consumption possibly via the activation of uncoupling processes, but its effect at the skeletal muscle level remains poorly documented and conflicting. To clarify this issue, gastrocnemius muscle function and energetics were investigated in mice 2 h after a single intake of either vehicle (control) or purified capsiate (at 10 or 100 mg/kg body wt) through a multidisciplinary approach combining in vivo and in vitro measurements. Mechanical performance and energy pathway fluxes were assessed strictly noninvasively during a standardized electrostimulation-induced exercise, using an original device implementing 31-phosphorus magnetic resonance spectroscopy, and mitochondrial respiration was evaluated in isolated saponin-permeabilized fibers. Compared with control, both capsiate doses produced quantitatively similar effects at the energy metabolism level, including an about twofold decrease of the mitochondrial respiration sensitivity for ADP. Interestingly, they did not alter either oxidative phosphorylation or uncoupling protein 3 gene expression at rest. During 6 min of maximal repeated isometric contractions, both doses reduced the amount of ATP produced from glycolysis and oxidative phosphorylation but increased the relative contribution of oxidative phosphorylation to total energy turnover (+28 and +21% in the 10- and 100-mg groups, respectively). ATP cost of twitch force generation was further reduced in the 10- (-35%) and 100-mg (-45%) groups. Besides, the highest capsiate dose also increased the twitch force-generating capacity. These data present capsiate as a helpful candidate to enhance both muscle performance and oxidative phosphorylation during exercise, which could constitute a nutritional approach for improving health and preventing obesity and associated metabolic disorders.

Muscle energetics changes throughout maturation: a quantitative 31P-MRS analysis.

We quantified energy production in 7 prepubescent boys (11.7 ± 0.6 yr) and 10 men (35.6 ± 7.8 yr) using (31)P-magnetic resonance spectroscopy to investigate whether development affects muscle energetics, given that resistance to fatigue has been reported to be larger before puberty. Each subject performed a finger flexions exercise at 0.7 Hz against a weight adjusted to 15% of their maximal voluntary strength for 3 min, followed by a 15-min recovery period. The total energy cost was similar in both groups throughout the exercise bout, whereas the interplay of the different metabolic pathways was different. At the onset of exercise, children exhibited a higher oxidative contribution (50 ± 15% in boys and 25 ± 8% in men, P < 0.05) to ATP production, whereas the phosphocreatine breakdown contribution was reduced (40 ± 10% in boys and 53 ± 12% in men, P < 0.05), likely as a compensatory mechanism. The anaerobic glycolysis activity was unaffected by maturation. The recovery phase also disclosed differences regarding the rates of proton efflux (6.2 ± 2.5 vs. 3.8 ± 1.9 mM · pH unit(-1) · min(-1), in boys and men, respectively, P < 0.05), and phosphocreatine recovery, which was significantly faster in boys than in men (rate constant of phosphocreatine recovery: 1.3 ± 0.5 vs. 0.7 ± 0.4 min(-1); V(max): 37.5 ± 14.5 vs. 21.1 ± 12.2 mM/min, in boys and men, respectively, P < 0.05). Our results obtained in vivo clearly showed that maturation affects muscle energetics. Children relied more on oxidative metabolism and less on creatine kinase reaction to meet energy demand during exercise. This phenomenon can be explained by a greater oxidative capacity, probably linked to a higher relative content in slow-twitch fibers before puberty.

Comparative analysis of skeletal muscle oxidative capacity in children and adults: a 31P-MRS study.

The aim of the present study was to compare the oxidative capacity of the forearm flexor muscles in vivo between children and adults using 31-phosphorus magnetic resonance spectroscopy. Seven boys (11.7 +/- 0.6 y) and 10 men (35.6 +/- 7.8 year) volunteered to perform a 3 min dynamic finger flexions exercise against a standardized weight (15% of the maximal voluntary contraction). Muscle oxidative capacity was quantified on the basis of phosphocreatine (PCr) post-exercise recovery kinetics analysis. End-of-exercise pH was not significantly different between children and adults (6.6 +/- 0.2 vs. 6.5 +/- 0.2), indicating that indices of PCr recovery kinetics can be reliably compared. The rate constant of PCr recovery (kPCr) and the maximum rate of aerobic ATP production were about 2-fold higher in young boys than in men (kPCr: 1.7 +/- 1.2 vs. 0.7 +/- 0.2 min(-1); Vmax: 49.7 +/- 24.6 vs. 29.4 +/- 7.9 mmol.L(-1).min(-1), p < 0.05). Our results clearly illustrate a greater mitochondrial oxidative capacity in the forearm flexor muscles of young children. This larger ATP regeneration capacity through aerobic mechanisms in children could be one of the factors accounting for their greater resistance to fatigue during high-intensity intermittent exercise.

Effect of maturation on the relationship between muscle size and force production.

PURPOSE: Although it is well accepted that an increase in muscle size is linked to an increase in muscle force, the relationship between muscle size and maximal strength during maturation is still discussed. In the present study we aimed at determining whether maturation affects the relationship between muscle size and maximal strength, and we investigated the reasons accounting for the discrepancies among previous studies. METHODS: Maximal isometric handgrip force (Fmax) and forearm muscle size were measured in 14 prepubertal boys (11.3 +/- 0.8 yr old), 16 adolescents (13.3 +/- 1.4 yr old), and 16 men (35.4 +/- 6.4 yr old). Anatomic maximal cross-sectional area (MCSA) and muscle volume (VM) were measured using MRI, and these results were compared with muscle volume (VL) obtained from anthropometric measurements. RESULTS: Fmax was linearly correlated with VM (r2 = 0.90), VL (r2 = 0.85), and MCSA (r2 = 0.87), while VM was strongly correlated with VL (r2 = 0.90). The Fmax/VM ratio did not differ among groups, whereas Fmax/VL and Fmax/MCSA ratios were significantly higher in adults than in children and adolescents. These results demonstrated that, when compared with MRI, anthropometric measurements led to a systematic overestimation of muscle volume. In addition, this overestimation was significantly larger in children (43.1%) and adolescents (38.5%) as compared with adults (20.5%) (P < 0.05). CONCLUSION: Our results showed that the maximal isometric strength exerted by the forearm muscles in humans is proportional to their size whatever the age, and that VM is the best index of muscle size during growth. The previously reported increased ability to produce maximal strength from childhood to adulthood could be explained by systematic bias introduced by the method used to characterize muscle size instead of physiological or neural changes.