Psychosocial and Social Environmental Factors as Moderators in the Relation between the Objective Environment and Older Adults' Active Transport.

In order to develop tailored interventions aiming to encourage active transport among older adults, it is important to gain insights into the modifiable moderators affecting active transport behavior considering the neighborhood in which one lives. Therefore, this study aimed to determine which objective physical environmental factors have an impact on the active transport behavior of Belgian older adults (≥65 years old) and which psychosocial and social environmental moderators influence those relationships. Data from 503 independent living older adults who participated the Belgian Environmental Physical Activity Study in Seniors were included. Multilevel negative binominal regression models (participants nested in neighborhoods) with log link function were fitted for the analyses. Our resulted indicated that older adults living in an environment with higher residential density, higher park density, lower public transport density, and more entropy index had higher active transport levels. Furthermore, different types of neighborhood in which older adults live can lead to different moderators that are decisive for increasing older adults' active transport behavior. Therefore, based on our results some recommendations towards tailored interventions could be given to increase older adults' active transport behavior depending on the environment in which one lives.

Decreasing cx36 gap junction coupling compensates for overactive KATP channels to restore insulin secretion and prevent hyperglycemia in a mouse model of neonatal diabetes.

Mutations to the ATP-sensitive K(+) channel (KATP channel) that reduce the sensitivity of ATP inhibition cause neonatal diabetes mellitus via suppression of ß-cell glucose-stimulated free calcium activity ([Ca(2+)]i) and insulin secretion. Connexin-36 (Cx36) gap junctions also regulate islet electrical activity; upon knockout of Cx36, ß-cells show [Ca(2+)]i elevations at basal glucose. We hypothesized that in the presence of overactive ATP-insensitive KATP channels, a reduction in Cx36 would allow elevations in glucose-stimulated [Ca(2+)]i and insulin secretion to improve glucose homeostasis. To test this, we introduced a genetic knockout of Cx36 into mice that express ATP-insensitive KATP channels and measured glucose homeostasis and islet metabolic, electrical, and insulin secretion responses. In the normal presence of Cx36, after expression of ATP-insensitive KATP channels, blood glucose levels rapidly rose to >500 mg/dL. Islets from these mice showed reduced glucose-stimulated [Ca(2+)]i and no insulin secretion. In mice lacking Cx36 after expression of ATP-insensitive KATP channels, normal glucose levels were maintained. Islets from these mice had near-normal glucose-stimulated [Ca(2+)]i and insulin secretion. We therefore demonstrate a novel mechanism by which islet function can be recovered in a monogenic model of diabetes. A reduction of gap junction coupling allows sufficient glucose-stimulated [Ca(2+)]i and insulin secretion to prevent the emergence of diabetes.

Dimensionality and size scaling of coordinated Ca(2+) dynamics in MIN6 ß-cell clusters.

Pancreatic islets of Langerhans regulate blood glucose homeostasis by the secretion of the hormone insulin. Like many neuroendocrine cells, the coupling between insulin-secreting ß-cells in the islet is critical for the dynamics of hormone secretion. We have examined how this coupling architecture regulates the electrical dynamics that underlie insulin secretion by utilizing a microwell-based aggregation method to generate clusters of a ß-cell line with defined sizes and dimensions. We measured the dynamics of free-calcium activity ([Ca(2+)]i) and insulin secretion and compared these measurements with a percolating network model. We observed that the coupling dimension was critical for regulating [Ca(2+)]i dynamics and insulin secretion. Three-dimensional coupling led to size-invariant suppression of [Ca(2+)]i at low glucose and robust synchronized [Ca(2+)]i oscillations at elevated glucose, whereas two-dimensional coupling showed poor suppression and less robust synchronization, with significant size-dependence. The dimension- and size-scaling of [Ca(2+)]i at high and low glucose could be accurately described with the percolating network model, using similar network connectivity. As such this could explain the fundamentally different behavior and size-scaling observed under each coupling dimension. This study highlights the dependence of proper ß-cell function on the coupling architecture that will be important for developing therapeutic treatments for diabetes such as islet transplantation techniques. Furthermore, this will be vital to gain a better understanding of the general features by which cellular interactions regulate coupled multicellular systems.

Effect of near-infrared light exposure on mitochondrial signaling in C2C12 muscle cells.

Near-infrared (NIR) light is a complementary therapy used to treat musculoskeletal injuries but the underlying mechanisms are unclear. Acute NIR light treatment (~800-950 nm; 22.8 J/cm(2)) induced a dose-dependent increase in mitochondrial signaling (AMPK, p38 MAPK) in differentiated muscle cells. Repeated NIR light exposure (4 days) appeared to elevate oxidative stress and increase the upstream mitochondrial regulatory proteins AMPK (3.1-fold), p38 (2.8-fold), PGC-1α (19.7%), Sirt1 (26.8%), and reduced RIP140 (23.2%), but downstream mitochondrial regulation/content (Tfam, NRF-1, Sirt3, cytochrome c, ETC subunits) was unaltered. Our data indicates that NIR light alters mitochondrial biogenesis signaling and may represent a mechanistic link to the clinical benefits.

Effects of exercise training on tumor hypoxia and vascular function in the rodent preclinical orthotopic prostate cancer model.

Regular physical exercise is considered to be an integral component of cancer care strategies. However, the effect of exercise training on tumor microvascular oxygenation, hypoxia, and vascular function, all of which can affect the tumor microenvironment, remains unknown. Using an orthotopic preclinical model of prostate cancer, we tested the hypotheses that, after exercise training, in the tumor, there would be an enhanced microvascular Po2, increased number of patent vessels, and reduced hypoxia. We also investigated tumor resistance artery contractile properties. Dunning R-3327 AT-1 tumor cells (10(4)) were injected into the ventral prostate of 4-5-mo-old male Copenhagen or Nude rats, which were randomly assigned to tumor-bearing exercise trained (TB-Ex trained; n = 15; treadmill exercise for 5-7 wk) or sedentary groups (TB-Sedentary; n = 12). Phosphorescence quenching was used to measure tumor microvascular Po2, and Hoechst-33342 and EF-5 were used to measure patent vessels and tumor hypoxia, respectively. Tumor resistance artery function was assessed in vitro using the isolated microvessel technique. Compared with sedentary counterparts, tumor microvascular Po2 increased ∼100% after exercise training (TB-Sedentary, 6.0 ± 0.3 vs. TB-Ex Trained, 12.2 ± 1.0 mmHg, P < 0.05). Exercise training did not affect the number of patent vessels but did significantly reduce tumor hypoxia in the conscious, resting condition from 39 ± 12% of the tumor area in TB-Sedentary to 4 ± 1% in TB-Ex Trained. Exercise training did not affect vessel contractile function. These results demonstrate that after exercise training, there is a large increase in the driving force of O2 from the tumor microcirculation, which likely contributes to the considerable reduction in tumor hypoxia. These results suggest that exercise training can modulate the microenvironment of the tumor, such that a sustained reduction in tumor hypoxia occurs, which may lead to a less aggressive phenotype and improve patient prognosis.

Short-term caloric restriction, resveratrol, or combined treatment regimens initiated in late-life alter mitochondrial protein expression profiles in a fiber-type specific manner in aged animals.

Aging is associated with a loss in muscle known as sarcopenia that is partially attributed to apoptosis. In aging rodents, caloric restriction (CR) increases health and longevity by improving mitochondrial function and the polyphenol resveratrol (RSV) has been reported to have similar benefits. In the present study, we investigated the potential efficacy of using short-term (6 weeks) CR (20%), RSV (50 mg/kg/day), or combined CR+ RSV (20% CR and 50 mg/kg/day RSV), initiated at late-life (27 months) to protect muscle against sarcopenia by altering mitochondrial function, biogenesis, content, and apoptotic signaling in both glycolytic white and oxidative red gastrocnemius muscle (WG and RG, respectively) of male Fischer 344 × Brown Norway rats. CR but not RSV attenuated the age-associated loss of muscle mass in both mixed gastrocnemius and soleus muscle, while combined treatment (CR + RSV) paradigms showed a protective effect in the soleus and plantaris muscle (P < 0.05). Sirt1 protein content was increased by 2.6-fold (P < 0.05) in WG but not RG muscle with RSV treatment, while CR or CR + RSV had no effect. PGC-1α levels were higher (2-fold) in the WG from CR-treated animals (P < 0.05) when compared to ad-libitum (AL) animals but no differences were observed in the RG with any treatment. Levels of the anti-apoptotic protein Bcl-2 were significantly higher (1.6-fold) in the WG muscle of RSV and CR + RSV groups compared to AL (P < 0.05) but tended to occur coincident with elevations in the pro-apoptotic protein Bax so that the apoptotic susceptibility as indicated by the Bax to Bcl-2 ratio was unchanged. There were no alterations in DNA fragmentation with any treatment in muscle from older animals. Additionally, mitochondrial respiration measured in permeabilized muscle fibers was unchanged in any treatment group and this paralleled the lack of change in cytochrome c oxidase (COX) activity. These data suggest that short-term moderate CR, RSV, or CR + RSV tended to modestly alter key mitochondrial regulatory and apoptotic signaling pathways in glycolytic muscle and this might contribute to the moderate protective effects against aging-induced muscle loss observed in this study.

The impact of aging on mitochondrial function and biogenesis pathways in skeletal muscle of sedentary high- and low-functioning elderly individuals.

Age-related loss of muscle mass and strength (sarcopenia) leads to a decline in physical function and frailty in the elderly. Among the many proposed underlying causes of sarcopenia, mitochondrial dysfunction is inherent in a variety of aged tissues. The intent of this study was to examine the effect of aging on key groups of regulatory proteins involved in mitochondrial biogenesis and how this relates to physical performance in two groups of sedentary elderly participants, classified as high- and low-functioning based on the Short Physical Performance Battery test. Muscle mass was decreased by 38% and 30% in low-functioning elderly (LFE) participants when compared to young and high-functioning elderly participants, respectively, and positively correlated to physical performance. Mitochondrial respiration in permeabilized muscle fibers was reduced (41%) in the LFE group when compared to the young, and this was associated with a 30% decline in cytochrome c oxidase activity. Levels of key metabolic regulators, SIRT3 and PGC-1α, were significantly reduced (50%) in both groups of elderly participants when compared to young. Similarly, the fusion protein OPA1 was lower in muscle from elderly subjects; however, no changes were detected in Mfn2, Drp1 or Fis1 among the groups. In contrast, protein import machinery components Tom22 and cHsp70 were increased in the LFE group when compared to the young. This study suggests that aging in skeletal muscle is associated with impaired mitochondrial function and altered biogenesis pathways and that this may contribute to muscle atrophy and the decline in muscle performance observed in the elderly population.

Contractile activity-induced gene expression in fast- and slow-twitch muscle.

Many proteins that function as transcription factors regulate the transcriptional activity of nuclear genes encoding mitochondrial proteins. Several of these are rapidly inducible with contractile activity, followed by a recovery phase. The aim of the present study was to evaluate the expression of a number of rapidly responding gene products to an acute bout of contractile activity followed by a recovery period in both slow- and fast-twitch muscle. Using an in vitro isolated muscle preparation, extensor digitorum longus (EDL) and soleus muscles were stimulated for 15 min, followed by 30 min recovery. Following stimulation, ATP levels were decreased in both the EDL and soleus (25% and 32%, respectively). We found that phosphorylation of p38 MAP kinase was elevated in both muscle types, with a more dramatic 3.5-fold increase observed in the EDL muscle. Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) mRNA expression was unchanged as a result of stimulation and recovery, while c-Fos transcript levels were decreased as a result of stimulation, but returned to resting values following recovery. Interestingly, nuclear respiratory factor 1 mRNA levels were unaffected by stimulation, but increased significantly (34%) during the recovery phase. These data suggest that the extent of the induction of transcription factor mRNA to acute exercise, which leads to subsequent muscle adaptations, is transcript specific and dependent on (i) the activation of upstream kinases, (ii) the muscle phenotype, and (iii) the duration of the recovery period.

Transcriptional and post-transcriptional regulation of mitochondrial biogenesis in skeletal muscle: effects of exercise and aging.

Acute contractile activity of skeletal muscle initiates the activation of signaling kinases. This promotes the phosphorylation of transcription factors, leading to enhanced DNA binding and transcriptional activation and/or repression. The mRNA products of nuclear genes encoding mitochondrial proteins are translated in the cytosol and imported into pre-existing mitochondria. When contractile activity is repeated, the recapitulation of these cellular events progressively leads to an expansion of the mitochondrial reticulum within muscle. This has physiologically relevant health benefit, including enhanced lipid metabolism and reduced muscle fatigability. In aging skeletal muscle, the response to contractile activity appears to be attenuated, suggesting that a greater contractile stimulus is required to attain a similar phenotype adaptation. This review summarizes our current understanding of the effects of exercise on the gene expression pathway leading to organelle biogenesis in muscle.