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In eight male patients with normal liver and kidney function fibrinolytic components were measured in arterial blood and in renal and hepatic vein blood, obtained during catheterization for analysis of hypertension. Blood samples were collected simultaneously from veins und corresponding arteries before and 5 minutes after the completion of intravenous injection of desmopressin (DDAVP), 0.4 micrograms/kg body weight over a 10 minute period. DDAVP induced a rise in t-PA antigen and activity, and in von Willebrand factor, accompanied by a decrease in free PA-inhibitor level. We failed to detect a significant rise in plasma urokinase activity. The concentrations of fibrinogen, plasminogen, alpha 2-antiplasmin, antithrombin III and coeruloplasmin did not change either. Renal production of t-PA under basal conditions was inferred from a negative arterio-venous (A-V) difference in t-PA-activity and in t-PA-antigen levels but this could not be confirmed by orthogonal regression analysis of the same data. A-V differences of other fibrinolytic factors were negligible. In the hepatic vessels a significant positive A-V difference of t-PA-activity and of t-PA-antigen levels was a uniform finding. After DDAVP, when plasma levels were elevated, the mean A-V difference was proportionally higher, consistent with a constant fractional elimination rate. Free PA-inhibitor was virtually absent from arterial blood after DDAVP, but appeared in hepatic vein blood, indicating either production of the inhibitor by the liver or dissociation of a circulating complex of t-PA and its inhibitor in the liver. The blood levels of the other investigated components did not show any change upon passage through the liver.(ABSTRACT TRUNCATED AT 250 WORDS)
Disk herniation is a primary cause of radicular back pain. The purpose of this study was to evaluate the antiallodynic effective dose in 50% of the sample (ED50) and dorsal root ganglion (DRG) protein modulation of a peripheral direct adenosine monophosphate kinase alpha (AMPKα) activator (O304) in a murine model of lumbar disk puncture.
The direct peripheral AMPK activator O304 reduced allodynia in a dose-dependent manner, and immunoblot studies of the DRG showed that O304 increased p-AMPK and decreased TRPA1, p-ERK1/2, as well as translation factors involved in neuroplasticity. Our findings confirm the role of peripheral AMPKα activation in modulating nociceptive pain.
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To maintain and restore skeletal muscle mass and function is essential for healthy aging. We have found that myonectin acts as a cardioprotective myokine. Here, we investigate the effect of myonectin on skeletal muscle atrophy in various male mouse models of muscle dysfunction. Disruption of myonectin exacerbates skeletal muscle atrophy in age-associated, sciatic denervation-induced or dexamethasone (DEX)-induced muscle atrophy models. Myonectin deficiency also contributes to exacerbated mitochondrial dysfunction and reduces expression of mitochondrial biogenesis-associated genes including PGC1α in denervated muscle. Myonectin supplementation attenuates denervation-induced muscle atrophy via activation of AMPK. Myonectin also reverses DEX-induced atrophy of cultured myotubes through the AMPK/PGC1α signaling. Furthermore, myonectin treatment suppresses muscle atrophy in senescence-accelerated mouse prone (SAMP) 8 mouse model of accelerated aging or mdx mouse model of Duchenne muscular dystrophy. These data indicate that myonectin can ameliorate skeletal muscle dysfunction through AMPK/PGC1α-dependent mechanisms, suggesting that myonectin could represent a therapeutic target of muscle atrophy.
Discrepancy between average life expectancy and healthy life expectancy is a serious social problem in aged societies worldwide. Age-associated loss of muscle mass and function, also known as sarcopenia, is one of the determinant factors for physical disability, thereby leading to adverse outcomes including poor quality of life and death1. Exercise training results in enhancement of muscle mass and function, and provides a benefit to sarcopenia. However, disabilities caused by age-associated complications including stroke, bone fracture and cancer-associated cachexia make exercise training impractical or inefficient among elderly patients. Thus, the development of therapeutic approaches to maintain and restore skeletal muscle mass and function could be indispensable for healthy aging.
Myonectin, also known as C1q/TNF-related protein 15/erythroferrone, acts as a muscle-derived secreted factor, also referred to as myokine, which is abundantly expressed in skeletal muscle tissue2,3. Myonectin has been reported to modulate fatty acid metabolism, iron metabolism, osteoblast and osteoclast differentiation and adipogenesis4,5,6,7,8. Recently we have reported that myonectin is an exercise-induced myokine which protects the heart from ischemia-reperfusion injury9. These findings indicated that myonectin affects nearby or remote organs in an endocrine manner to maintain whole body homeostasis. However, the impact of myonectin on skeletal muscle function and disease in an autocrine manner has not been clarified. Here, we investigated whether myonectin modulates skeletal muscle function in various mouse models of muscle dysfunction including age-related sarcopenia.
We investigated whether muscle myonectin expression is modulated by aging process. The mRNA and protein levels of myonectin (Fam132b) in soleus and gastrocnemius muscle tissues were significantly lower in 80-week-old (aged) WT mice than in 20-week-old (young) WT mice (Fig. 1a and Supplementary Fig. 1). To investigate whether myonectin contributes to the skeletal muscle mass and function in aged mice, muscle weight and strength in young and aged myonectin-knockout (KO) mice were evaluated. The weights of gastrocnemius and soleus muscle tissues divided by body weights were significantly lower in aged myonectin-KO mice than in aged WT mice, whereas there were no significant differences in muscle weights between young WT and young myonectin-KO mice (Fig. 1b). Aged myonectin-KO mice exhibited increased body weight compared with aged WT mice, while body weight did not differ between young WT and young myonectin-KO mice (Supplementary Fig. 2a). Gastrocnemius muscle weight was significantly lower in aged myonectin-KO mice than in aged-WT mice (Supplementary Fig. 2a). Soleus muscle weight seemed to be lower in aged myonectin-KO mice than in aged WT mice, but this was not statistically significant. There were no significant differences in gastrocnemius muscle and soleus muscle weights between young WT and young myonectin-KO mice.
Consistently, mean cross-sectional area (CSA) of gastrocnemius muscle tissues was significantly smaller in aged myonectin-KO mice than in aged WT mice, whereas there were no differences in CSA of gastrocnemius muscle tissues between young WT and young myonectin-KO mice (Fig. 1c). Consistently, aged myonectin-KO mice showed the smaller size distribution of gastrocnemius muscle CSA compared with aged WT mice (Fig. 1c). In addition, mean CSA of type II muscle fibers in gastrocnemius muscle was significantly smaller in aged myonectin-KO mice than in aged WT mice (Supplementary Fig. 3a, b). There were no differences in mean CSA of type I muscle fibers in gastrocnemius muscle between aged WT and aged myonectin-KO mice (Supplementary Fig. 3a, b). Aged myonectin-KO mice exhibited the increased frequency of smaller type II fiber CSA compared with aged WT mice, whereas the distribution of type I fiber cross-sectional area did not differ between aged WT and aged myonectin-KO mice (Supplementary Fig. 3b). Aged WT mice had the increased frequency of type I fibers in gastrocnemius muscle compared with young WT mice, and aged myonectin-KO mice exhibited the reduced frequency of type I fibers compared with aged WT mice (Supplementary Fig. 3c).
Furthermore, aged myonectin-KO mice showed the significant reduction of maximal force of grip strength in 4 limbs and fore 2 limbs, which was normalized by body weight, as compared with aged WT mice (Fig. 1d). Aged myonectin-KO mice also had the significant reduction of non-normalized maximal force of grip strength in 4 limbs compared with aged WT mice (Supplementary Fig. 2b). Non-normalized maximal force of grip strength in fore 2 limbs seemed to be lower in aged myonectin-KO mice than in aged WT mice, but this was not statistically significant. The maximal force of grip strength in 4 limbs and fore 2 limbs, which was normalized by muscle weight did not differ between aged WT and aged myonectin-KO mice. There were no significant differences in maximal force of grip strength in 4 limbs and fore 2 limbs, which was non-normalized or normalized by body weight or muscle weight, between young WT and young myonectin-KO mice. In voluntary wheel running test, aged myonectin-KO mice exhibited remarkable reduction of average number of rotations compared with aged WT mice (Fig. 1e). Thus, myonectin reduction could promote muscle atrophy and dysfunction in aged mice.
To further investigate the roles of myonectin in muscle atrophy, myonectin-KO and WT mice were subjected to denervation-induced or dexamethasone (DEX)-induced muscle atrophy. Myonectin protein levels in gastrocnemius muscle tissues were significantly reduced in denervation-operated and DEX-treated WT mice compared with sham WT mice (Supplementary Fig. 4a). At 5 days after sciatic nerve denervation, the weights of denervated gastrocnemius and soleus muscle tissues normalized by body weights were significantly lower in myonectin-KO mice than in WT mice (Fig. 2a). There were no significant differences in body weight, denervated gastrocnemius muscle weight and denervated soleus muscle weight between WT and myonectin-KO mice (Supplementary Fig. 2c). There were no significant differences in the weights of non-denervated gastrocnemius and soleus muscle tissues, which was non-normalized or normalized by body weights between WT and myonectin-KO mice (Fig. 2a and Supplementary Fig. 2c).
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