Abstract

To determine the efficacy and potential protective mechanism of canagliflozin combined with aerobic exercise in treating chronic heart failure (CHF). Isoproterenol was injected into rats to create CHF models. The rats were then subsequently divided into saline, canagliflozin (3 mg/kg/d), aerobic exercise training, and canagliflozin combined with aerobic exercise training. Compared to the CHF group, the canagliflozin combined with the aerobic exercise group had superior ventricular remodeling and cardiac function. In rats treated with canagliflozin combined with aerobic exercise, the expression of cytochrome P450 (CYP) 4A3, CYP4A8, COL1A1, COL3A1, and FN1 was reduced, while the expression of CYP26B1, ALDH1A2, and CYP1A1 increased significantly. Additionally, canagliflozin combined with aerobic exercise decreased the phosphorylation of AKT and ERK1/2. Canagliflozin combined with aerobic exercise has a positive effect on the development of CHF via the regulation of retinol metabolism and the AKT/ERK signaling pathway.

Introduction

Chronic heart failure (CHF), the most prevalent form of cardiovascular illness, is a global health issue with a high death and morbidity rate.1 The disease affects about 2% of the adult population worldwide, and the 5-year mortality rate is estimated to be between 45 and 60%.2 CHF is a complex condition characterized by a cardiac muscle’s inability to maintain blood supply to peripheral tissues, resulting in decreased systemic energy metabolism.3 Multiple studies have demonstrated that regulating cardiac energy metabolism is critical for treatment.4,5 The β-oxidation of fatty acids in the mitochondria satisfies the heart’s high energy requirements. Oliveros et al. observed previously observed that a vitamin A deficit paired antioxidant defenses, promoted lipid peroxidation in the adult rat heart, and altered aortic lipid metabolism.6 The peroxisome proliferator-activated receptor (PPAR) is a ligand-activated nuclear transcription factor.7 PPAR modulates fatty acid oxidation (FAO) and mitochondrial bioenergetics, suppresses myocardial remodeling and fibrosis, and improves HF.8 Consequently, we must investigate new techniques for enhancing cardiac function by ameliorating abnormalities of cardiac energy metabolism, preventing cardiac remodeling and fibrosis, and thereby preventing or postponing the advancement of heart failure.

Canagliflozin, an inhibitor of sodium-glucose cotransporter 2 (SGLT-2), has been demonstrated to benefit HF with a lower ejection fraction.9 SGLT-2 inhibitors (canagliflozin, and so forth) for patients with CHF, improve the quality of life, and reduce mortality, morbidity, and readmission rates.10 In diabetic and nondiabetic subjects, canagliflozin treatment significantly reduced the risk of cardiovascular death, myocardial infarction, and hospitalization for hypertension.11 In addition, SGLT-2 inhibitors can improve fatty acid metabolism and utilize ketone bodies to create mitochondrial energy, so enhancing the aerobic metabolism of skeletal muscle, inhibiting anaerobic metabolism, and enhancing aerobic exercise capacity.12 Canagliflozin has been demonstrated to decrease myocardial glucose metabolism, enhance myocardial fatty acid metabolism, and increase the circulation of ketone bodies,13 thereby ameliorating heart failure via modifying myocardial energy metabolism and oxidative stress.14

Results

Canagliflozin combined with aerobic exercise improved isoproterenol-induced cardiac dysfunction
To investigate the effect of canagliflozin combined with aerobic exercise on CHF, cardiac function was assessed using echocardiography. After 10 days of ISO administration, the levels of LVEF (p < 0.001) and LVFS (p < 0.001) in the ISO group were significantly lower than in the control group, indicating that the CHF rat model was successfully established. LVEF and LVFS levels were significantly higher in the ISO+CA group (LVEF, p < 0.05; LVFS, p < 0.05), the ISO+AE group (LVEF, p < 0.05; LVFS, p < 0.05), and the ISO+AE+CA group (LVEF, p < 0.01; LVFS, p < 0.01). Moreover, compared to the ISO group, the levels of LVIDs (p < 0.05) and LVESV (p < 0.05) were significantly reduced in the ISO+AE+CA group but not in the ISO+CA group (LVIDs, p = 0.21; LVESV, p = 0.21). (Figures 1A and 1B, Table 1).

In short-duration endurance events, such as middledistance running and sprint cross-country skiing, performance is not only related to the rate of aerobic energy supply but also to anaerobic energy provision (Duffield et al., 2005; Losnegard et al., 2012). This is also the case, at least to some extent, during longer-duration endurance events performed over undulating terrains and at fluctuating intensities, since the oxygen uptake (VO˙ 2) demand will at times exceed the maximal oxygen uptake (VO˙ 2max) (Norman et al., 1989; Skiba et al., 2012). In comparison to aerobic energy supply, anaerobic energy supply has a far more limited capacity (i.e., limited amount of energy that can be produced anaerobically) but can provide adenosine triphosphate at a much faster rate than the oxidative pathway. Therefore, the relative contribution of anaerobic energy production decreases with exercise duration (Gastin, 2001). In highly-trained runners, for example, anaerobic metabolism has been shown to account for ∼34 and ∼16% of the total energy turnover during 800-m and 1500-m events (lasting ∼1:53 and ∼3:55 min), respectively (Spencer and Gastin, 2001). In addition to energy supply, the efficacy of converting metabolic energy to external work (i.e., gross efficiency, GE) is an important component of endurance performance (Joyner and Coyle, 2008). Energetic contributions from aerobic pathways during wholebody exercise can easily be quantified using measurements of VO˙ 2, while a direct quantification of the anaerobic energy yield is more complicated and only possible via sophisticated, invasive and expensive technologies (Bangsbo et al., 1990). Therefore, a common approach during whole-body exercise is to indirectly estimate anaerobic energy production using the maximal accumulated oxygen (O2) deficit (MAOD) method (Medbø et al., 1988), which is based on calculating a linear relationship between submaximal VO˙ 2 and speed (or power output) and estimating VO˙ 2 demand at supramaximal speeds by extrapolation.

برنامه تمرین تناوبی با شدت بالا ( HIIT ( با توجه به اثرات بالقوه آن بر میزان تمرین و مدت زمان لازم، به شکل فزاینده ای به روش محبوب از ورزش تبدیل شده است.. این تحقیق تأثیرات دو پروتکل HIIT را به ازای آموزش حالت پایدار بر روی ظرفیت هوازی و بی هوازی در ادامه 8 هفته آموزش مقایسه نموده است . 55 نفر از افراد در سن دانشگاه به طور تصادفی برای سه گروه آموزشی تعیین شدند ( هر هفته 3 گروه ) . گروه حالت پایدار ( 19 n= ) ورزش نموده ( چرخه کارسنج ) 20 دقیقه در 90 % آستانه تهویه VT . گروه تاباتا ( 21n= ) هشت فاصله زمانی به مدت s20 را در s10 باقیمانده / VO2 ماکزیمم 170 % کامل نمودند . گروه مایر ( 15n= ) 13 سری به مدت s30 ( 20 دقیقه ) ، بازیابی s60 / VO2 P ماکزیمم 100 % @ ، میانگین VT 90 % = PO را کامل نمودند . هر فرد 24 جلسه آموزشی را طی 8 هفته طی کرد . نتایج : افزایش قابل توجهی ( 05/ < p ) درVO2 ماکزیمم ( 19 + ، 18 + و 18 % + ) و PPO ( 17 + ، 24 + و 14 % ) برای هر گروه آموزشی و همچنین افزایش قابل توجهی در پیک ( اوج ) ( 8 + ، 9 + و 5 % ) و میانگین ( 4 + ، 7 + و 6 % ) نیرو طی آزمایش وینگیت ( Wingate ) وجود داشت ، اما هیچگونه تفاوت مهمی بین گروهها وجود نداشت . اندازه گیریهای لذت برنامه آموزشی نشان داد که پروتکل تاباتا به میزان قابل توجهی نسبت به پروتکل های حالت پایدار و مایر کمتر لذت بخش است ( 05 / < p ) ، و اینکه لذت بخشی تمام گروهها در سراسر دوره تحقیق کاهش یافت ( 05/ p ) . نتایج بدست آمده ، این نظریه را ارائه می کنند که اگرچه پروتکل های HIIT دارای صرفه جویی زمانی می باشند ، آنها برای آموزش ورزش معمولی در جوانان کم تحرک برتر نمی باشند .

مقدمه :
علاقمندی در بهینه سازی میزان انطباق ، حاصل از آموزش فیزیکی است ، در حالی که به حداقل رساندن زمان و تلاش انجام شده برای آموزش ، موضوع قابل توجهی در حیطه جامعه ورزشی می باشد . از جمله مطالعات کلاسیک مدت آموزش برای عملکرد ورزشی ( Astrand و همکاران ، 1960 ؛ Muller ، 1953 ) بدنه اساسی شواهد در ارتباط با آثار و عوارض تفاوتهای در تکرار ، شدت ، زمان و تجویز می باشد ( Pescatello و همکاران ، 2014 ) . این شواهد بعداً در توصیه های بهداشت عمومی گسترده بیان می شود که بزرگسالان سالم می بایستی 30 دقیقه ورزش با شدت معتدل را در اکثر روزهای هفته و اگر چه نه همه روزهای هفته داشته باشند ( Haskell و همکاران ، 2007 ) ، و اینکه افراد علاقمند به افزایش پیامدها ( شامل عملکرد رقابتی ) می بایستی به طور منظم حجم بالای از آموزش و و آموزش با شدت بالاتری را بگذرانند ( Billat ، 2001 ؛ Selier و همکاران ، 2013 ) . طراحی تحقیقات فعال ادامه یافت تا تعیین کند که چه تغییرات خاصی از HIIT ممکن است انطباق های با آموزش ورزش را بیشتر بهینه سازد . نوشتجات ، بویژه با اشاره به برنامه تمرین تناوبی با شدت بالا ( HIIT ) ، اخیراً مورد بررسی قرار گرفته اند ( Buchiet و Laursen ، a2013 ؛ b2013 ؛ Kessler و همکاران ، 2012 ؛ Weston و همکاران ، 2014 ) .