<p>Parathyroid hormone (PTH) is the major physiological regulator of the extracellular Ca²⁺ concentration ([Ca²⁺]_o) in the body. The secretion of this hormone is suppressed at high [Ca²⁺]_o. Previously this was thought to occur by intracellular degradation of the hormone in the secretory pathway of parathyroid (PT) cells but is now believed to result from extracellular Ca²⁺ stimulus-secretion coupling via the calcium sensing receptor (CaR). In contrast to the stimulation of PTH secretion upon inhibition of mature PTH proteolysis, inhibition of PT proteasomes caused the accumulation of PTH precursors and inhibited secretion of PTH. This suggests that PT proteasomes play a quality control function in the maturation of PTH but they do not directly participate in the [Ca²⁺]_o-regulated secretion of the hormone. Treatment of PT cells with 12-O-tetradecanyolphorbol-13-acetate (TPA) blocks the high [Ca²⁺]_o-induced CaR-mediated suppression of PTH secretion. To delineate the role of DAG-responsive protein kinase C (PKC) isoforms in this process, we complemented pharmacological modulation of PKC activity with physiological activation of the enzyme via the CaR. PKC-α was rapidly activated by high [Ca²⁺]_o and was efficiently down-regulated by prolonged TPA treatment. In CaR-transfected HEK293 cells, TPA and high [Ca²⁺]_o induced the activation of ERK1/2 but the TPA effect was CaR- and Ca²⁺-independent. The magnitude of neomycin-induced release of Ca²⁺ from intracellular stores following pharmacological modulation of PKC activity was opposite to that resulting from physiological activation/inhibition of the enzyme via the CaR. Influx of Ca²⁺ following activation of the receptor occurred by store-operated mechanisms. Over-expression of wt or DN PKC-α or-ε in PT cells using the Tet-On adenovirus gene delivery system revealed that the stimulatory effect of TPA on PTH secretion at high [Ca²⁺]_o was enhanced in cells over-expressing wt PKC-α, but the coupling of the extracellular Ca²⁺ signal to PTH secretion was not dependent on the physiological activation of this PKC isoform via the CaR.</p>

Parathyroid hormone (PTH) is the major physiological regulator of the extracellular Ca2+ concentration ([Ca2+]o) in the body. The secretion of this hormone is suppressed at high [Ca2+]o. Previously this was thought to occur by intracellular degradation of the hormone in the secretory pathway of parathyroid (PT) cells but is now believed to result from extracellular Ca2+ stimulus-secretion coupling via the calcium sensing receptor (CaR). In contrast to the stimulation of PTH secretion upon inhibition of mature PTH proteolysis, inhibition of PT proteasomes caused the accumulation of PTH precursors and inhibited secretion of PTH. This suggests that PT proteasomes play a quality control function in the maturation of PTH but they do not directly participate in the [Ca2+]o-regulated secretion of the hormone. Treatment of PT cells with 12-O-tetradecanyolphorbol-13-acetate (TPA) blocks the high [Ca2+]o-induced CaR-mediated suppression of PTH secretion. To delineate the role of DAG-responsive protein kinase C (PKC) isoforms in this process, we complemented pharmacological modulation of PKC activity with physiological activation of the enzyme via the CaR. PKC-α was rapidly activated by high [Ca2+]o and was efficiently down-regulated by prolonged TPA treatment. In CaR-transfected HEK293 cells, TPA and high [Ca2+]o induced the activation of ERK1/2 but the TPA effect was CaR- and Ca2+-independent. The magnitude of neomycin-induced release of Ca2+ from intracellular stores following pharmacological modulation of PKC activity was opposite to that resulting from physiological activation/inhibition of the enzyme via the CaR. Influx of Ca2+ following activation of the receptor occurred by store-operated mechanisms. Over-expression of wt or DN PKC-α or-ε in PT cells using the Tet-On adenovirus gene delivery system revealed that the stimulatory effect of TPA on PTH secretion at high [Ca2+]o was enhanced in cells over-expressing wt PKC-α, but the coupling of the extracellular Ca2+ signal to PTH secretion was not dependent on the physiological activation of this PKC isoform via the CaR.

The membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) is an important signaling molecule as substrate for the phospholipase C (PLC)-catalyzed formation of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol, and by directly regulating e.g. ion-channels, the cytoskeleton and vesicle trafficking in various types of cells. The present studies provide insights into the regulation of PLC activity and the plasma membrane concentration of PIP2 in individual insulin-secreting cells. Real-time monitoring of plasma membrane PIP2 was performed with evanescent wave microscopy and the PIP2/IP3-binding pleckstrin-homology-domain from PLC-δ1 fused to GFP. It was demonstrated that membrane depolarization and voltage-dependent Ca2+ influx are sufficient to activate PLC. Rise of the glucose concentration triggered Ca2+-dependent activation of PLC. Simultaneous measurements of the cytoplasmic Ca2+ concentration ([Ca2+]i) demonstrated that oscillations of [Ca2+]i resulting from periodic influx induced cyclic activation of PLC. Activation of muscarinic receptors caused a biphasic PLC response with an initial peak enhanced by positive feedback by Ca2+ mobilized from intracellular stores, followed by sustained activity depending on store-operated Ca2+-entry. Activation of PLC by Ca2+ mobilized from intracellular stores was part of the Ca2+-induced Ca2+ release mechanism by which glucagon stimulates primary mouse pancreatic β-cells. Experiments in permeabilized cells demonstrated rapid turnover of PIP2 with t1/2 ~ 16s. ATP stimulated concentration-dependent synthesis of plasma membrane PIP2, counteracted by the ADP analogue ADPβS. RT-PCR analysis identified transcripts of 10 different phosphoinositide-kinases. The ATP-stimulated PIP2 formation was mediated by type II and III PI4-kinases as well as by PIP5-kinase Iβ. It is concluded that the PIP2 concentration in the plasma membrane is regulated by the ATP/ADP ratio and that its hydrolysis by PLC is tightly controlled by [Ca2+]i in insulin-secreting cells.

cAMP and Ca2+ are key regulators of exocytosis in many cells, including insulin-secreting pancreatic β-cells. Glucose-stimulated insulin secretion from β-cells is pulsatile and driven by oscillations of the cytoplasmic Ca2+ concentration ([Ca2+]i), but little is known about the kinetics of cAMP signaling and the mechanisms of cAMP action. Evanescent wave microscopy and fluorescent translocation biosensors were used to monitor plasma membrane-related signaling events in single MIN6-cells and primary mouse β-cells. Glucose stimulation of insulin secretion resulted in pronounced oscillations of the membrane phospholipid PIP3 caused by autocrine activation of insulin receptors. Glucose also triggered oscillations of the sub-plasma membrane cAMP concentration ([cAMP]pm). These oscillations were preceded and enhanced by elevations of [Ca2+]i, but conditions raising cytoplasmic ATP triggered [cAMP]pm elevations without accompanying changes in [Ca2+]i. The [cAMP]pm oscillations were also synchronized with PIP3 oscillations and both signals were suppressed after inhibition of adenylyl cyclases. Protein kinase A (PKA) was important for promoting concomitant initial elevations of [cAMP]pm and [Ca2+]i, and PKA inhibitors diminished the PIP3 response when applied before glucose stimulation, but did not affect already manifested PIP3 oscillations. The glucose-induced PIP3 oscillations were markedly suppressed in cells treated with siRNA against the cAMP-dependent guanine nucleotide exchange factor Epac2. Pharmacological activation of Epac restored PIP3 responses after adenylyl cyclase or PKA inhibition. Glucose and other cAMP-elevating stimuli induced redistribution of fluorescence-tagged Epac2 from the cytoplasm to the plasma membrane. This translocation was modulated by [Ca2+]i and depended on intact cyclic nucleotide-binding and Ras-association domains. In conclusion, glucose generates cAMP oscillations in β-cells via a concerted action of Ca2+ and metabolically generated ATP. The oscillations are important for the magnitude and kinetics of insulin secretion. While both protein kinase A and Epac is required for initiation of insulin secretion the cAMP-dependence of established pulsatility is mediated by Epac2.

No description available.

Made available in DSpace on 2015-07-22T20:49:59Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-11-24. Added 1 bitstream(s) on 2015-08-11T03:26:31Z : No. of bitstreams: 1 Publico-474.pdf: 1648088 bytes, checksum: ac90101ea1d6072c64d4dd6e9a18d152 (MD5) / Justificativa: O presente trabalho aborda os efeitos de novos inibidores de acetilcolinesterase (AChE) na reatividade farmacológica e neurotransmissão em ratos e camundongos. Os novos anticolinesterásicos, ITH12118 e ITH12117, têm estrutura híbrida, derivada da molécula do anticolinesterásico Tacrina e da 1,4 diidropiridina nimodipina, inibidor de canal de Ca2+ do tipo L. O objetivo da síntese foi obter fármacos candidatos para o tratamento da Doença de Alzheimer. Materiais e métodos. Os experimentos de contração foram feitos inicialmente para comparar a ação de ITH12118 e ITH12117 com Fisostigmina, Tacrina, e Nimodipina em ductos deferentes de ratos (DDR) e camundongos (DDC) em curva concentração-efeito (CCE) para acetilcolina (ACh), avaliando-se os parâmetros efeito máximo (Emax), dose eficaz 50 (DE50), afinidade aparente (pD2), relação de doses (Dose Ratio, DR) para avaliar a potencialização da resposta da ACh pelos inibidores de AChE e responsividade relativa (&#61554;) para avaliar o efeito máximo do receptor de ACh. Para estudar o papel do Ca2+ foram feitas curvas cumulativas e tempo-efeito para o íon na presença dos inibidores de AChE ou nimodipina, além da medida de Ca2+ citosólico com sonda fluorescente FURA-2AM. Realizou-se também curvas por estimulação elétrica transmural para estudar o efeito sobre a contração neurogênica. CCE para NA também foram feitas. Além disso, foi medida a atividade da enzima AChE em microplaca, na presença dos inibidores. Foram feitos testes após o tratamento in vivo com Fisostigmina, e testes de aprendizado e memória em camundongos após tratamento com Tacrina e ITH12118. Resultados. Por alteração de DR, observou-se maior potenciação das curvas de ACh pela Fisostigmina, seguido da Tacrina e ITH12118 em DDR e discreta potenciação na presença de Fisostigmina e Tacrina em DDC. Entretanto, o Emax das curvas de ACh caiu drasticamente na presença dos anticolinesterásicos em DDR e em DDC, na presença de ITH12118 e ITH12117. Os experimentos para Ca2+ evidenciaram uma inibição significativa com a Nimodipina e ITH12118 em DDR, sendo que em DDC o ITH12117 também bloqueou a contração. Em relação à contração por estímulos elétricos, observamos somente bloqueio da fase tônica por ITH12118. Os experimentos em microplaca mostraram inibição da AChE pela Fisostigmina e Tacrina em DDR, DDC e SNC (córtex) de rato e camundongo, com inibição da enzima pelos compostos ITH12118 e ITH12117 somente em maiores concentrações. Em córtex de rato e camundongo, ITH12118 e ITH12117 mostraram maior potência de inibição. Observou-se maior proporção de BuChE em DDR, e experimentos preliminares de contração induzida com ACh realizados na presença de Iso-OMPA, inibidor seletivo de BuChE, e Fisostigmina, mostraram que a diminuição do Emax é menor que na presença de Fisostigmina isoladamente. A CCE para NA foi bloqueada em DDR pela Nimodipina e ITH12118, e em DDC pela Nimodipina, ITH12118 e ITH12117. Após tratamento in vivo, CCE para ACh não foram deslocadas. A avaliação de memória e aprendizado não apresentou diferenças em relação aos controles, porém houve tendência de maior retenção de memória após Tacrina e ITH12118. Conclusões. A potenciação da ACh no eixo das doses é coerente com o mecanismo de inibição da colinesterase pelos antagonistas. Entretanto ainda merece explicação a redução observada no Emax. Conforme os experimentos de contração, os compostos ITH12118 e ITH12117 apresentaram maior potência como bloqueadores de canal de Ca2+ do que como anticolinesterásicos. Os achados em relação às diferenças entre DDR e DDC parecem ser relacionadas à maior concentração de BuChE em DDR, mas esta observação deve ser melhor investigada. / Justification: The present work considers the effects of new inhibitors of acetylcholinesterase (AChE) on the reactivity and neurotransmission in rats and mice. The new anticholinesterase compounds, ITH12118 and ITH12117, have an hybrid stucture, derived from the molecule of of the anticholinesterase Tacrine and the 1,4 dihydropyridine nimodipine, a blocker of l-type calcium channel blocker. The objective of the syntesis was to obtain drugs as candidates for the theatment of Alzheimer’s disease. Material and Methods: Contraction experiments were initialy made to compare de actions of ITH12118 and ITH12117 with that of Physostigmine, Tacrine and Nimodipine in vas deferens of rats (RVD) and mice (MVD) on concentration-response curves (CRC) for ACh, for the measurement of the folowwing parameters: maximum effect (Emax), 50% effective dose (ED50), aparent affinity (pD2), dose ratio for agonist (DR) to evaluate the potentiation by cholinesterase blockers, intrinsic activity (a) of agonists and relative responsiveness (&#61554;) to evaluate the maximum effect of ACh receptor. For the study of the role of calcium, cumulative and time-response curves for this ion were made, in the presence of cholinesterase blockers and Nimodipine, besides the measurement of cytosolic calcium by means of fluorescent FURA-2AM. In addition, curves for transmural electrical stimulation were also made for the study of neurogenic contractions. CRC for NA were also made. Furthermore, the activity of the enzyme AchE was also analysed in microplates, in the presence of blockers. Finaly, tests after treatment in vivo were made for Physostigmine and tests for learning and memory of mice, after treatment with Tacrine and ITH12118. Results: After measuments of DR, we have observer a higher potentiation of the curves of ACh by Physostigmine, followed by Tacrine and ITH12118 in RVD, and a slght potentiation by Physostigmine and Tacrine in MVD. However, the Emax of the CRC for ACh was greatly decreased in the presence of anticholinesterase blockers in RVD and and in MVD after ITH12118 and ITH12117. The experiments with Ca2+ showed a significant block by Nimodipine and ITH12118 in RVD, and by ITH12117 in MVD. In relation to the contraction by electrical transmural stimulation, just a block of tonic contraction was induced by ITH12118. The experiments in microplates showed a block of AChH by Fisotigmine and Tacrine in RVD and MVD, and in rat and mouse in Central Nervous Sistem, with a blockade by higher concentrations of ITH12118 and ITH12117. In rat and mouse cortex ITH12118 and ITH12117 showed a higher potency of blockade. A higher proportion of BuChE was shown in RVD, and in preliminary contraction experiments with Iso-OMPA, a selective blocker of BuChE, and Physostigmine, showed that a reduction of Emax is lower in the presence of Physostigmine isolatedly. The curves for NA were blocked in RVD by Nimodipine and ITH12118 and by Nimodipine, ITH12118 and ITH12117 in MVD. After treatment in vivo, the curves for ACh were not displaced. The evaluation of learning and memory did not show significant differences from controls, but a tendency for a higher retention of memory was presented after Tacrine and ITH12117. Conclusions: The potentiation of ACh in the dosis axis is within the expectations for the block of cholinesterase by the antagonists. However, the decrease of Emax needs further investigation. According to the contraction experiments, compounds ITH12118 and ITH12117 showed a higher potency as blockers of calcium channels than of cholinesterase. The changes between RVD and MVD seem to be related to the higher concentration of BuChE in RVD, but this point needs additional investigation. / TEDE

Submitted by NATHÁLIA DE SOUZA PARREIRAS null (nathaliaparreiras@ig.com.br) on 2017-08-04T14:35:24Z No. of bitstreams: 1 tese nathalia 04-08-17 para impressão.pdf: 1835096 bytes, checksum: 83b6c0e6cef99c4619caafcd238490f8 (MD5) / Approved for entry into archive by LUIZA DE MENEZES ROMANETTO (luizamenezes@reitoria.unesp.br) on 2017-08-04T20:20:09Z (GMT) No. of bitstreams: 1 parreiras_ns_dr_bot.pdf: 1835096 bytes, checksum: 83b6c0e6cef99c4619caafcd238490f8 (MD5) / Made available in DSpace on 2017-08-04T20:20:09Z (GMT). No. of bitstreams: 1 parreiras_ns_dr_bot.pdf: 1835096 bytes, checksum: 83b6c0e6cef99c4619caafcd238490f8 (MD5) Previous issue date: 2017-06-08 / O cálcio é um nutriente essencial às plantas, participando das funções estruturais da parede celular e da membrana, como contra cátion para ânions orgânicos e inorgânicos no vacúolo e desempenha papel essencial como mensageiro intracelular no citosol. A concentração de cálcio no citoplasma das células vegetais aumenta em resposta a várias condições de desenvolvimento e fatores ambientais. Essas alterações na concentração de cálcio no citosol da célula são cruciais para as respostas fisiológicas da planta. O presente estudo objetivou avaliar se a aplicação de concentrações de cloreto de cálcio afetam as trocas gasosas, atividade das enzimas antioxidantes, perfil químico do óleo essencial extraído das folhas, tamanho, firmeza e aspectos químicos ligados à qualidade dos frutos de Annona × atemoya Mabb. cv. ‘Thompson’. O experimento foi conduzido no sítio Paraizinho localizado no munícipio de Pardinho-SP em pomar comercial. O delineamento experimental foi em blocos casualisados, sendo quatro concentrações de cloreto de cálcio (0%, 0,5%, 1,0% e 1,5% de CaCl2) aplicados via foliar a cada 45 dias e seis blocos, com uma planta por parcela experimental. Foram avaliadas as seguintes características: trocas gasosas, enzimas antioxidantes, diâmetro e comprimento dos frutos, firmeza, pH, acidez titulável, sólidos solúveis, relação sólidos solúveis/acidez, açúcares, amido, teor de ácido ascórbico,teor de cálcio, perfil químico dos óleos essenciais. As dosagens de CaCl2 aumentaram a assimilação de CO2, a eficiência no uso da água, a eficiência de carboxilação, a firmeza e a acidez dos frutos, reduzindo os teores de ácido ascórbico e modificando o perfil químico dos óleos essenciais. / Calcium is an essential nutrient for plants, participating in the structural functions of the cell wall and membrane, as against cation for organic and inorganic anions in the vacuole and plays an essential role as a messenger in intracellular cytosol. The concentration of calcium in the cytoplasm of plant cells increases in response to several conditions of development and environmental factors. These changes in the concentration of calcium in the cytosol of the cell are crucial to the physiological responses of the plant. The present study aimed to evaluate the implementation of different calcium concentrations in gas exchange, chemical profile of essential oil extracted from the leaves, size, firmness and chemical aspects linked to the quality of the Annona × atemoya Mabb The experiment was conducted at the Paraisinho site located in the municipality of Pardinho-SP in a commercial orchard. The experimental design was in randomized blocks, being 4 concentrations of calcium chloride (0%, 0.5%, 1.0% and 1.5% CaCl2) applied via by foliar every 45 days and six replications of a plant. The effect of the treatments was evaluated by assessing the following: gas exchange, diameter and length of fruits, firmness, pH, soluble solids, titratable acidity, soluble solids/acidity, sugars, starch, ascorbic acid content and chemical profile of essential oils. The levels of CaCl2 increased CO2 assimilation, water use efficiency, carboxylation efficiency, the firmness and the acidity of the fruit, reducing the levels of Ascorbic acid and modifying the chemical profile of essential oils.

Recentemente foi demonstrado que na insuficiência cardíaca (IC), a via final das doenças circulatórias e a maior causa de internação em idosos no Brasil, os danos morfo-funcionais da musculatura esquelética representam um preditor independente de mortalidade. Por outro lado, é conhecido que o treinamento físico aeróbico previne o aparecimento desses prejuízos, que potencialmente podem ter relação com alterações no transporte intracelular de Ca2+. Nesse sentido, o objetivo principal do presente estudo foi avaliar o efeito da IC e do treinamento físico aeróbico na IC em relação à função da musculatura esquelética, à expressão de proteínas que transportam Ca2+ no sóleo e no plantar (DHPR&alpha;1, DHPR &alpha;2, DHPR &beta;1, RYR, NCX, SERCA 1, SERCA 2, parvalbumina) e à atividade da via proteolítica dependente deste íon nestes músculos (calpaína e calpastatina). Foram utilizados camundongos machos C57B7/6J controle e com inativação dos genes para os receptores &alpha;2A e &alpha;2C adrenérgicos com 7 meses de idade, quando estes apresentam IC induzida por hiperatividade simpática e 50% de mortalidade. A função muscular foi avaliada pelos testes de deambulação e resistência à inclinação. Tanto a expressão protéica como a atividade proteolítica foram avaliadas por Western blot. Os animais com IC apresentaram disfunção muscular, prejuízos nas proteínas relacionadas ao transiente de Ca2+ tanto no sóleo como no plantar, além de alterações na via proteolítica dependente deste íon em relação aos controle. O treinamento físico, por sua vez, preveniu o aparecimento dessas alterações funcionais e moleculares nos animais com IC. Em conclusão, o treinamento físico aeróbico mostrou-se uma terapia efetiva para a síndrome / Heart failure (HF) is a clinical syndrome with poor prognosis characterized by exercise intolerance, early fatigue and skeletal muscle myopathy, which has been considered an independent predictor of mortality. Conversely, aerobic exercise training prevents skeletal muscle dysfunction, which might be related to altered intracellular Ca2+ handling. Therefore, we tested whether HF would lead to alterations in skeletal musculature function related to changes in Ca2+ handling proteins expression (DHPR&alpha;1, DHPR &alpha;2, DHPR &beta;1, RYR, NCX, SERCA 1, SERCA 2, parvalbumin) and activity of the Ca2+-dependent proteolysis (calpain and calpastatin) in soleus and plantaris muscles. The potential role of exercise training in preventing Ca2+ handling alterations was also studied. Male wild type and &alpha;2A e &alpha;2C adrenoceptor knockout (KO) mice on a C56BL/6J genetic background were studied at 7 months of age, when KO mice display HF and skeletal muscle myopathy associated with sympathetic hyperactivity and 50% of mortality. KO mice displayed skeletal muscle dysfunction paralleled by altered Ca2+ handling protein expression and Ca2+- induced proteolysis in both soleus and plantaris. Interestingly, exercise training prevented skeletal muscle dysfunction and Ca2+-induced proteolysis in both soleus and plantaris. Collectively, we provide evidence that improved net balance of Ca2+ handling proteins and decreased Ca2+-induced proteolysis upon exercise training is, at least in part, a compensatory mechanism against skeletal muscle myopathy of sympathetic hyperactivity-induced HF

No description available.

Recentemente foi demonstrado que na insuficiência cardíaca (IC), a via final das doenças circulatórias e a maior causa de internação em idosos no Brasil, os danos morfo-funcionais da musculatura esquelética representam um preditor independente de mortalidade. Por outro lado, é conhecido que o treinamento físico aeróbico previne o aparecimento desses prejuízos, que potencialmente podem ter relação com alterações no transporte intracelular de Ca2+. Nesse sentido, o objetivo principal do presente estudo foi avaliar o efeito da IC e do treinamento físico aeróbico na IC em relação à função da musculatura esquelética, à expressão de proteínas que transportam Ca2+ no sóleo e no plantar (DHPR&alpha;1, DHPR &alpha;2, DHPR &beta;1, RYR, NCX, SERCA 1, SERCA 2, parvalbumina) e à atividade da via proteolítica dependente deste íon nestes músculos (calpaína e calpastatina). Foram utilizados camundongos machos C57B7/6J controle e com inativação dos genes para os receptores &alpha;2A e &alpha;2C adrenérgicos com 7 meses de idade, quando estes apresentam IC induzida por hiperatividade simpática e 50% de mortalidade. A função muscular foi avaliada pelos testes de deambulação e resistência à inclinação. Tanto a expressão protéica como a atividade proteolítica foram avaliadas por Western blot. Os animais com IC apresentaram disfunção muscular, prejuízos nas proteínas relacionadas ao transiente de Ca2+ tanto no sóleo como no plantar, além de alterações na via proteolítica dependente deste íon em relação aos controle. O treinamento físico, por sua vez, preveniu o aparecimento dessas alterações funcionais e moleculares nos animais com IC. Em conclusão, o treinamento físico aeróbico mostrou-se uma terapia efetiva para a síndrome / Heart failure (HF) is a clinical syndrome with poor prognosis characterized by exercise intolerance, early fatigue and skeletal muscle myopathy, which has been considered an independent predictor of mortality. Conversely, aerobic exercise training prevents skeletal muscle dysfunction, which might be related to altered intracellular Ca2+ handling. Therefore, we tested whether HF would lead to alterations in skeletal musculature function related to changes in Ca2+ handling proteins expression (DHPR&alpha;1, DHPR &alpha;2, DHPR &beta;1, RYR, NCX, SERCA 1, SERCA 2, parvalbumin) and activity of the Ca2+-dependent proteolysis (calpain and calpastatin) in soleus and plantaris muscles. The potential role of exercise training in preventing Ca2+ handling alterations was also studied. Male wild type and &alpha;2A e &alpha;2C adrenoceptor knockout (KO) mice on a C56BL/6J genetic background were studied at 7 months of age, when KO mice display HF and skeletal muscle myopathy associated with sympathetic hyperactivity and 50% of mortality. KO mice displayed skeletal muscle dysfunction paralleled by altered Ca2+ handling protein expression and Ca2+- induced proteolysis in both soleus and plantaris. Interestingly, exercise training prevented skeletal muscle dysfunction and Ca2+-induced proteolysis in both soleus and plantaris. Collectively, we provide evidence that improved net balance of Ca2+ handling proteins and decreased Ca2+-induced proteolysis upon exercise training is, at least in part, a compensatory mechanism against skeletal muscle myopathy of sympathetic hyperactivity-induced HF