**1. Introduction**

Obesity is a chronic disease of preventable multifactorial origin; it is the fifth main risk factor for human death globally. It is a pathological state that impairs skeletal muscle [1,2], characterized by a decrease in the force of contraction, a reduced capacity to withstand fatigue, and cell damage [3].

Fat accumulation alters carbohydrates and lipids metabolism, which affects the normal contractile function [4], decrease in glucose uptake, and deterioration of the insulin signaling pathway, causing insulin resistance [5]. Together, it favors the development of fatigue [6], decreased mitochondrial respiration and ATP production, as well as an increase in mitochondrial production of reactive oxygen species (ROS) [7].

Opening of the ATP-sensitive potassium channels (KATP channels) has been identified as a defense mechanism to counter muscle fatigue and metabolic stress; in the cell membrane and the inner membrane of the mitochondria [8], and play an important role as sensors of intracellular ATP and ADP ratio [9], closing when ATP levels are high and opening when ADP levels increase [10]. Several studies have shown that KATP channels play an essential role in tissue protection [11,12], where the channel becomes crucial in preventing contractile dysfunction and fiber damage caused by oxidative stress [13].

KATP channels can be activated pharmacologically, making them an important target for myoprotection [14,15]. Diazoxide is a vasodilator and an inhibitor of insulin secretion. It is considered a drug that is beneficial for some pathologies, such as obesity, since it reduces intake of food and weight gain, prevents hyperinsulinemia, improves insulin sensitivity, and improves blood glucose and lipid profile, which together counteracts mitochondrial dysfunction [16,17].

Diazoxide, reported as a selective opener for mitoKATP channels, delays fatigue in mammalian fast skeletal muscle fibers [18]. Similarly, increased post-fatigue force in the slow skeletal muscle has been observed by diazoxide and nicorandil, another KATP channel opener, [19,20] and both, protects skeletal muscle against ischemia-reperfusion injury [15].

Exercise is a non-pharmacological treatment for metabolic disorders associated with obesity. It has been reported that it increases the expression of KATP channels [13] and promotes various metabolic adaptations in skeletal muscle [21]. Exercise decreases the fat stored in the muscle which improves muscle contraction, increases insulin sensitivity which prevents hyperinsulinemia and stimulates the transport of glucose into the cell [22], and increases antioxidant defenses through a hormonal mechanism which makes the muscle more resistant to oxidative stress [23]. Together these mechanisms protect against mitochondrial dysfunction through lower ROS levels by improving respiration and promoting beta-oxidation of fatty acids [7,24].

Therefore, we hypothesized that diazoxide and exercise improve muscle function in obesity by decreasing oxidative stress. Obesity and its effect on skeletal muscle have been extensively studied, as has exercise to counteract its adverse effects, while the opening of the KATP channels has been studied as a mechanism of muscular protection. However, this is the first study that shows how diazoxide, exercise, and the combination of both, improve the contraction and function of muscle fibers in obesity by reducing oxidative stress.
