Following myocardial infarction, nonischemic myocyte death results in infarct expansion, myocardial loss, and ventricular dysfunction. Here, we demonstrate that a specific proapoptotic gene, Bnip3, minimizes ventricular remodeling in the mouse, despite having no effect on early or late infarct size. We evaluated the effects of ablating Bnip3 on cardiomyocyte death, infarct size, and ventricular remodeling after surgical ischemia/reperfusion (IR) injury in mice. Immediately following IR, no significant differences were observed between Bnip3(-/-) and WT mice. However, at 2 days after IR, apoptosis was diminished in Bnip3(-/-) periinfarct and remote myocardium, and at 3 weeks after IR, Bnip3(-/-) mice exhibited preserved LV systolic performance, diminished LV dilation, and decreased ventricular sphericalization. These results suggest myocardial salvage by inhibition of apoptosis. Forced cardiac expression of Bnip3 increased cardiomyocyte apoptosis in unstressed mice, causing progressive LV dilation and diminished systolic function. Conditional Bnip3 overexpression prior to coronary ligation increased apoptosis and infarct size. These studies identify postischemic apoptosis by myocardial Bnip3 as a major determinant of ventricular remodeling in the infarcted heart, suggesting that Bnip3 may be an attractive therapeutic target.

Normal production of RBCs requires that the antiapoptotic protein Bcl-xl be induced at end stages of differentiation in response to erythropoietin (Epo) signaling. The critical proapoptotic pathways inhibited by Bcl-xl in erythroblasts are unknown. We used gene targeting in the mouse to evaluate the BH3-only factor Nix, which is transcriptionally up-regulated during Epo-stimulated in vitro erythrocyte differentiation. Nix null mice are viable and fertile. Peripheral blood counts revealed a profound reticulocytosis and thrombocytosis despite normal serum Epo levels and blood oxygen tension. Nix null mice exhibited massive splenomegaly, with splenic and bone marrow erythroblastosis and reduced apoptosis in vivo during erythrocyte maturation. Hematopoietic progenitor populations were unaffected. Cultured Nix null erythroid cells were hypersensitive to Epo and resistant to apoptosis stimulated by cytokine deprivation and calcium ionophore. Transcriptional profiling of Nix null spleens revealed increased expression of cell cycle and erythroid genes, including Bcl-xl, and diminished expression of cell death and B cell-related genes. Thus, cell-autonomous Nix-mediated apoptosis in opposition to the Epo-induced erythroblast survival pathway appears indispensable for regulation of erythrocyte production and maintenance of hematological homeostasis. These results suggest that physiological codependence and coordinated regulation of pro-and antiapoptotic Bcl2 family members may represent a general regulatory paradigm in hematopoiesis.apoptosis ͉ Bcl2 proteins ͉ erythropoietin ͉ polycythemia vera

Neurons can respond to decreased network activity with a homeostatic increase in the amplitudes of miniature EPSCs (mEPSCs). The prevailing view is that mEPSC amplitudes are uniformly multiplied by a single factor, termed "synaptic scaling." Deviations from purely multiplicative scaling have been attributed to biological differences, or to a distortion imposed by a detection threshold limit. Here, we demonstrate in neurons dissociated from cortices of male and female mice that the shift in mEPSC amplitudes observed in the experimental data cannot be reproduced by simulation of uniform multiplicative scaling, with or without the distortion caused by applying a detection threshold. Furthermore, we demonstrate explicitly that the scaling factor is not uniform but is close to 1 for small mEPSCs, and increases with increasing mEPSC amplitude across a substantial portion of the data. This pattern was also observed for previously published data from dissociated mouse hippocampal neurons and dissociated rat cortical neurons. The finding of "divergent scaling" shifts the current view of homeostatic plasticity as a process that alters all synapses on a neuron equally to one that must accommodate the differential effect observed for small versus large mEPSCs. Divergent scaling still accomplishes the essential homeostatic task of modifying synaptic strengths in the opposite direction of the activity change, but the consequences are greatest for those synapses which individually are more likely to bring a neuron to threshold. Significance Statement In homeostatic plasticity, the responses to chronic increases or decreases in network activity act in the opposite direction to restore normal activity levels. Homeostatic plasticity is likely to play a role in diseases associated with long-term changes in brain function, such as epilepsy and neuropsychiatric illnesses. One homeostatic response is the increase in synaptic strength following a chronic block of activity. Research is focused on finding a globally expressed signaling pathway, because it has been proposed that the plasticity is uniformly expressed across all synapses. Here, we show that the plasticity is not uniform. Our work suggests that homeostatic signaling molecules are likely to be differentially expressed across synapses.

This study investigated whether regular alpine skiing could reverse sarcopenia and muscle weakness in older individuals. Twenty-two older men and women (67 ± 2 years) underwent 12 weeks of recreational skiing, two to three times a week, each session lasting ∼ 3.5 h. An age-matched, inactive group (n=20, 67 ± 4 years) served as a control (CTRL). Before and after the training period, knee extensors muscle thickness (T(m) ), pennation angle (θ) and fascicle length (L(f) ) of the vastus lateralis muscle were measured by ultrasound. Maximum isokinetic knee extensor torque (MIT) at an angular velocity of 60°/s was measured by dynamometry. After the training, T(m) increased by 7.1% (P<0.001), L(f) by 5.4% (P<0.02) and θ by 3.4% (P<0.05). The increase in T(m) was matched by a significant gain in MIT (13.3%, P<0.001). No significant changes, except for a decrease in θ (2.1%, P<0.02), were found in the CTRL group. The gain in T(m) in the training group correlated significantly with an increase in the focal adhesion kinase content, pointing to a primary role of this mechano-sensitive protein in sarcomere remodeling with muscle hypertrophy. Overall, the results show that alpine skiing is an effective intervention for combating sarcopenia and weakness in old age.

Strain is one of the parameters determining tendon adaptation to mechanical stimuli. The aim of this study was to test whether the patellar tendon strain induced during recreational alpine skiing would affect tendon mechanical properties in older individuals. Twenty-two older males and females (67 ± 2 years) were assigned to a 12-week guided skiing programme (IG) and 20 aged-matched volunteers served as controls (CG). Patellar tendon mechanical properties and cross-sectional area (CSA) were measured before and after training, with combined dynamometry and ultrasonography scanning. None of the variables changed significantly in the CG after training. In the IG, tendon stiffness and Young's modulus were increased (respectively, 14% and 12%, P<0.01), without any significant change in tendon CSA. In addition, changes in tendon stiffness were blunted in women (9%) compared with men (19%). Serum IGF-1 concentration tended to be lower in women (-19%, P=0.07). These results demonstrate that the mechanical stimulus induced by alpine skiing is sufficient to elicit adaptive changes in patellar tendon mechanical and material properties in older subjects. Furthermore, the present sex-specific adaptations are consistent with previous reports of lower collagen metabolic responsiveness in women and may be underpinned by anthropometric and metabolic differences.