Novel investigational drugs mimicking exercise for the treatment of cachexia

Abstract

Introduction: Cachexia is a syndrome characterized by body weight loss, muscle wasting, and metabolic abnormalities, that frequently complicates the management of people affected by chronic diseases. No effective therapy is actually available, although several drugs are under clinical evaluation. Altered energy metabolism markedly contributes to the pathogenesis of cachexia; it can be improved by exercise, able to both induce anabolism and inhibit catabolism.Areas covered in this review: This review will focus on exercise mimetics and on their potential inclusion in combined protocols to treat cachexia, with particular reference to the cancer-associated one.Expert opinion: Despite exercise improves muscle phenotype, most patients retain sedentary habits quite difficult to disrupt. Moreover, they frequently present with chronic fatigue and co-morbidities that reduce exercise tolerance. For these reasons drugs mimicking exercise could be beneficial also in the absence of patient compliance to the practice of physical activity. Different exercise mimetics are now available and, yet some of them may exert serious side-effects, investigating their effectiveness on muscle phenotype will provide a new tool for the management of cachexia.4

Moderate exercise in mice improves cancer plus chemotherapy‐induced muscle wasting and mitochondrial alterations

“…Among the potential approaches to counteract cancer cachexia, exercise was proposed because it impinges on several organs and targets tumor‐induced alterations. Whereas resistance exercise primarily increases the amount of contractile proteins resulting in a hypertrophic phenotype, endurance exercise induces several metabolic adaptations, including increased oxidative capacity and decreased inflammatory status (41). In this regard, we previously reported an improved muscle oxidative metabolism in C26‐bearing mice exercised on a treadmill, even though body and muscle wasting were not counteracted (9).…”

“…In this regard, taking into consideration the limiting factors that may interfere with exercise, different studies have demonstrated the effectiveness of a combined approach, merging the training activity with antianemia treatments or nutritional support (9, 50). Moreover, for those subjects that are exercise intolerant, an alternative strategy could be the administration of exercise mimetics (41), even if these drugs are not able to fully recapitulate the effects of exercise.…”

Muscle mitochondria and oxidative metabolism as targets against cancer cachexia

“…In addition, exercise performed in late-stage cachexia reduces the survival of C26-bearing mice exposed to chemotherapy [21] . Given these premises, strategies that circumvent the limitations of exercise or improve exercise capacity could be useful for cancer hosts who are intolerant to physical training [44] [ Figure 1].…”

“…One of the most relevant player in the exercise-induced adaptations in the skeletal muscle is the cotranscription factor PGC-1α, that responds to energy demand by enhancing the transcription of genes involved in mitochondrial biogenesis and turnover, leading to increased muscle oxidative capacity [44,45] . In this regard, the ablation of PGC-1α in mice has been shown to blunt the increase of autophagy and mitophagy induced by exercise, to decrease mitochondrial mass and to impair exercise performance [45,46] .…”

“…The modulations triggered by exercise may be mimicked by pharmacological and dietary compounds [44,56] . Some of them have been extensively studied, such as 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR), glitazones, metformin and sirtuin 1 (SIRT1) activators, also reporting their effectiveness in preventing cancer-induced muscle wasting [10,44] . Also erythropoietin (EPO), an endogenous cytokine essential for the growth and differentiation of red blood progenitor cells, has shown some exercise-like effects that go beyond the increase in oxygen delivery.…”