Aging is associated with reduced muscle mass (sarcopenia) and poor bone quality (osteoporosis), which together increase the incidence of falls and bone fractures. It is widely appreciated that aging triggers systemic oxidative stress, which can impair myoblast cell survival and differentiation. We previously reported that arginase plays an important role in oxidative stress-dependent bone loss. We hypothesized that arginase activity is dysregulated with aging in muscles and may be involved in muscle pathophysiology. To investigate this, we analyzed arginase activity and its expression in skeletal muscles of young and aged mice. We found that arginase activity and arginase 1 expression were significantly elevated in aged muscles. We also demonstrated that SOD2, GPx1, and NOX2 increased with age in skeletal muscle. Most importantly, we also demonstrated elevated levels of peroxynitrite formation and uncoupling of eNOS in aged muscles. Our in vitro studies using C2C12 myoblasts showed that the oxidative stress treatment increased arginase activity, decreased cell survival, and increased apoptotic markers. These effects were reversed by treatment with an arginase inhibitor, 2(S)-amino-6-boronohexanoic acid (ABH). Our study provides strong evidence that L-arginine metabolism is altered in aged muscle and that arginase inhibition could be used as a novel therapeutic target for age-related muscle complications.
With age, joints become subject to chronic inflammatory processes that lead to degeneration of articular cartilage. Although multifactorial, cytokines have been shown to play a role in the pathogenesis of these chronic disease states. Stromal cell-derived factor 1 (SDF-1) is a chemokine that has been shown to be active in homeostatic mechanisms and developmental processes throughout the body, such as endochondral bone formation. SDF-1 plays a role in the transition from cartilage to bone. Although it has been shown to be a factor in normal development, it has also been shown to involve in the pathogenesis of rheumatoid arthritis (RA) and osteoarthritis (OA). In RA, SDF-1 has been shown to stimulate the recruitment of proinflammatory cells, as well as osteoclasts to the synovium, aiding in the facilitation of synovial degradation. Similarly, in OA, SDF-1 has been shown to regulate key proteins involved in the degradation of the cartilage of the joint. Because of its role in degenerative joint disease, SDF-1 has been investigated as a potential therapeutic target. Animal studies have been employing SDF-1 inhibitors, such as AMD3100 and T140, to study their effects on attenuating degenerative joint disease. These studies have shown promising results in slowing the progression of cartilage degradation and could potentially be used as therapeutic target for humans OA and RA.
The age-related increase of the tryptophan metabolite, kynurenine (KYN), has been associated with osteoporosis progression. Increased activity of by Indoleamine-(2,3)-dioxygenase(IDO), are responsible for the elevation of KYN levels in bone tissue. IDO activity is elevated with age and could be a promising therapeutic target forosteopenia and osteoporosis. Previously, our group has shown that the serum level of KYN is elevated with age and correlates with bone loss in vivo. Kynurenine suppress the expression and activity of chemokine CXCL12 essential for osteogenesis, bone marrow stem cells homing. Bone Marrow Stem Cells (BMSC) cultured in 1% FBS were treated with CXCL12 (100ng/ml) in the presence of saline control or the autophagic flux-inhibition agent chloroquine (CQ). CXCL12 treatment increased autophagy by upregulating the degree of LC3B-II by 20%. CXCL12 treatment also significantly increased co-localization of LC3B and LAMP-2 in serum starved cells. In the present study, we tested the theory that kynurenine plays an opposite role to CXCL12 by suppressing the autophagy cell survival pathway and by inducing apoptosis. Treatment of nutrient-deprived murine BMSCs with 10 or 100 µM of KYN suppresses autophagy in a dose dependent fashion while increasing cellular apoptosis. Treatment of BMSCs with KYN downregulated autophagic flux in BMSC preventing CQ-induced CL3B/LAMP-2 colocalization. KYN treatment prevented conversion of LC3B-I to LC3B-II in CQ-treated cells by 30 percent. At the same time, KYN treatment induces apoptosis, by increasing TUNEL-positive cells number by more than 50 percent. Additionally, KYN treatment significantly increased the levels of cleaved isoforms of PARP and caspase-3.
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