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BackgroundExercise train (ET) stimulates muscle response in pathological conditions, including aging. The molecular mechanisms by which exercise improves impaired adiponectin/adiponectin receptor 1 (AdipoR1)‐related muscle actions associated with aging are poorly understood. Here we observed that in a senescence‐accelerated mouse prone 10 (SAMP10) model, long‐term ET modulated muscle‐regenerative actions.Methods25‐week‐old male SAMP10 mice were randomly assigned to the control and the ET (45 min/time, 3/week) groups for 4 months. Mice that were maintained in a sedentary condition served controls.ResultsET ameliorated aging‐related muscle changes in microstructure, mitochondria, and performance. The amounts of proteins or mRNAs for p‐AMPKα, p‐Akt, p‐ERK1/2, p‐mTOR, Bcl‐XL, p‐FoxO3, peroxisome proliferators‐activated receptor‐γ coactivator, adiponectin receptor1 (adpoR1), and cytochrome c oxidase‐IV, and the numbers of CD34+/integrin‐α7 + muscle stem cells (MuSCs) and proliferating cells in the muscles and bone‐marrow were enhanced by ET, whereas the levels of p‐GSK‐3α and gp91phox proteins and apoptotic cells were reduced by ET. The ET also resulted in increased levels of plasma adiponectin and the numbers of bone‐marrow (BM)‐derived circulating CD34+/integrin‐α7 + MuSCs and their functions. Integrin‐α7 + MuSCs of exercised mice had improved changes of those beneficial molecules. These ET‐mediated aged muscle benefits were diminished by adiponectin and AdipoR1 blocking as well as AMPK inhibition. Finally, recombinant mouse adiponectin enhanced AMPK and mTOR phosphorylations in BM‐derived integrin‐α7 + cells.ConclusionsThese findings suggest that ET can improve aging‐related impairments of BM‐derived MuSC regenerative capacity and muscle metabolic alterations via an AMPK‐dependent mechanism that is mediated by an adiponectin/AdipoR1 axis in SAMP10 mice.

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BackgroundExposure to psychosocial stress is a risk factor for cardiovascular disease, including vascular aging and regeneration. Given that dipeptidyl peptidase‐4 (DPP4) regulates several intracellular signaling pathways associated with the glucagon‐like peptide‐1 (GLP‐1) metabolism, we investigated the role of DPP4/GLP‐1 axis in vascular senescence and ischemia‐induced neovascularization in mice under chronic stress, with a special focus on adiponectin ‐mediated peroxisome proliferator activated receptor‐γ/its co‐activator 1α (PGC‐1α) activation.Methods and ResultsSeven‐week‐old mice subjected to restraint stress for 4 weeks underwent ischemic surgery and were kept under immobilization stress conditions. Mice that underwent ischemic surgery alone served as controls. We demonstrated that stress impaired the recovery of the ischemic/normal blood‐flow ratio throughout the follow‐up period and capillary formation. On postoperative day 4, stressed mice showed the following: increased levels of plasma and ischemic muscle DPP4 and decreased levels of GLP‐1 and adiponectin in plasma and phospho‐AMP‐activated protein kinase α (p‐AMPKα), vascular endothelial growth factor, peroxisome proliferator activated receptor‐γ, PGC‐1α, and Sirt1 proteins and insulin receptor 1 and glucose transporter 4 genes in the ischemic tissues, vessels, and/or adipose tissues and numbers of circulating endothelial CD31+/c‐Kit+ progenitor cells. Chronic stress accelerated aortic senescence and impaired aortic endothelial sprouting. DPP4 inhibition and GLP‐1 receptor activation improved these changes; these benefits were abrogated by adiponectin blocking and genetic depletion.ConclusionsThese results indicate that the DPP4/GLP‐1‐adiponectin axis is a novel therapeutic target for the treatment of vascular aging and cardiovascular disease under chronic stress conditions.

BackgroundDPP4 (Dipeptidyl peptidase‐4)‐GLP‐1 (glucagon‐like peptide‐1) and its receptor (GLP‐1R) axis has been involved in several intracellular signaling pathways. The Adrβ3 (β3‐adrenergic receptor)/CXCL12 (C‐X‐C motif chemokine 12) signal was required for the hematopoiesis. We investigated the novel molecular requirements between DPP4‐GLP‐1/GLP‐1 and Adrβ3/CXCL12 signals in bone marrow (BM) hematopoietic stem cell (HSC) activation in response to chronic stress.Methods and ResultsMale 8‐week‐old mice were subjected to 4‐week intermittent restrain stress and orally treated with vehicle or the DPP4 inhibitor anagliptin (30 mg/kg per day). Control mice were left undisturbed. The stress increased the blood and brain DPP4 levels, the plasma epinephrine and norepinephrine levels, and the BM niche cell Adrβ3 expression, and it decreased the plasma GLP‐1 levels and the brain GLP‐1R and BM CXCL12 expressions. These changes were reversed by DPP4 inhibition. The stress activated BM sca‐1highc‐Kithigh CD48low CD150high HSC proliferation, giving rise to high levels of blood leukocytes and monocytes. The stress‐activated HSC proliferation was reversed by DPP4 depletion and by GLP‐1R activation. Finally, the selective pharmacological blocking of Adrβ3 mitigated HSC activation, accompanied by an improvement of CXCL12 gene expression in BM niche cells in response to chronic stress.ConclusionsThese findings suggest that DPP4 can regulate chronic stress‐induced BM HSC activation and inflammatory cell production via an Adrβ3/CXCL12‐dependent mechanism that is mediated by the GLP‐1/GLP‐1R axis, suggesting that the DPP4 inhibition or the GLP‐1R stimulation may have applications for treating inflammatory diseases.

BackgroundCathepsin K (CatK) is a widely expressed cysteine protease that has gained attention because of its enzymatic and non‐enzymatic functions in signalling. Here, we examined whether CatK‐deficiency (CatK−/−) would mitigate injury‐related skeletal muscle remodelling and fibrosis in mice, with a special focus on inflammation and muscle cell apoptosis.MethodsCardiotoxin (CTX, 20 μM/200 μL) was injected into the left gastrocnemius muscle of male wild‐type (CatK+/+) and CatK−/− mice, and the mice were processed for morphological and biochemical studies.ResultsOn post‐injection Day 14, CatK deletion ameliorated muscle interstitial fibrosis and remodelling and performance. At an early time point (Day 3), CatK−/− reduced the lesion macrophage and leucocyte contents and cell apoptosis, the mRNA levels of monocyte chemoattractant protein‐1, toll‐like receptor‐2 and toll‐like receptor‐4, and the gelatinolytic activity related to matrix metalloproteinase‐2/‐9. CatK deletion also restored the protein levels of caspase‐3 and cleaved caspase‐8 and the ratio of the BAX to the Bcl‐2. Moreover, CatK deficiency protected muscle fibre laminin and desmin disorder in response to CTX injury. These beneficial muscle effects were mimicked by CatK‐specific inhibitor treatment. In vitro experiments demonstrated that pharmacological CatK inhibition reduced the apoptosis of C2C12 mouse myoblasts and the levels of BAX and caspase‐3 proteins induced by CTX.ConclusionsThese results demonstrate that CatK plays an essential role in skeletal muscle loss and fibrosis in response to CTX injury, possibly via a reduction of inflammation and cell apoptosis, suggesting a novel therapeutic strategy for the control of skeletal muscle diseases by regulating CatK activity.

Background Although apoptosis and cell proliferation have been extensively investigated in atherosclerosis and restenosis postinjury, the communication between these 2 cellular events has not been evaluated. Here, we report an inextricable communicative link between apoptosis and smooth muscle cell proliferation in the promotion of vascular remodeling postinjury. Methods and Results Cathepsin K–mediated caspase‐8 maturation is a key initial step for oxidative stress–induced smooth muscle cell apoptosis. Apoptotic cells generate a potential growth‐stimulating signal to facilitate cellular mass changes in response to injury. One downstream mediator that cathepsin K regulates is PLF‐1 (proliferin‐1), which can potently stimulate growth of surviving neighboring smooth muscle cells through activation of PI3K/Akt/p38MAPK (phosphatidylinositol 3‐kinase/protein kinase B/p38 mitogen‐activated protein kinase)‐dependent and ‐independent mTOR (mammalian target of rapamycin) signaling cascades. We observed that cathepsin K deficiency substantially mitigated neointimal hyperplasia by reduction of Toll‐like receptor‐2/caspase‐8–mediated PLF ‐1 expression. Interestingly, PLF ‐1 blocking, with its neutralizing antibody, suppressed neointima formation and remodeling in response to injury in wild‐type mice. Contrarily, administration of recombinant mouse PLF ‐1 accelerated injury‐induced vascular actions. Conclusions This is the first study detailing PLF ‐1 as a communicator between apoptosis and proliferation during injury‐related vascular remodeling and neointimal hyperplasia. These data suggested that apoptosis‐driven expression of PLF ‐1 is thus a novel target for treatment of apoptosis‐based hyperproliferative disorders.