Disrupted Skeletal Muscle Mitochondrial Dynamics, Mitophagy, and Biogenesis during Cancer Cachexia: A Role for Inflammation

Abstract

Chronic inflammation is a hallmark of cancer cachexia in both patients and preclinical models. Cachexia is prevalent in roughly 80% of cancer patients and accounts for up to 20% of all cancer-related deaths. Proinflammatory cytokines IL-6, TNF-α, and TGF-β have been widely examined for their regulation of cancer cachexia. An established characteristic of cachectic skeletal muscle is a disrupted capacity for oxidative metabolism, which is thought to contribute to cancer patient fatigue, diminished metabolic function, and muscle mass loss. This review's primary objective is to highlight emerging evidence linking cancer-induced inflammation to the dysfunctional regulation of mitochondrial dynamics, mitophagy, and biogenesis in cachectic muscle. The potential for either muscle inactivity or exercise to alter mitochondrial dysfunction during cancer cachexia will also be discussed.

Figure 1

Cancer cachexia-induced inflammation regulates mitochondria. Chronic inflammation during cancer cachexia is associated with increased circulatory proinflammatory cytokines IL-6, TNF-α, and TGF-β. Chronic inflammation through these cytokines has been demonstrated to decrease mitochondrial biogenesis through decreased activation of PGC-1a, NRF-1, and Sirt-1. Increased autophagy is apparent in cachectic muscle through inducing LC3B, Beclin-1, p62, Atg 5, and Bnip3 and dysregulating dynamics shown by increased FIS-1 and Drp-1 and decreased MFN-1, MFN-2, and OPA-1. These factors contribute to decreased mitochondrial function and ATP synthesis. The figure was made with Servier Medical Art (http://www.servier.com/Powerpoint-image-bank).

Figure 2

Mitochondrial dysfunction in skeletal muscle negatively regulates muscle mass. Elevated IL-6, TNF-α, and TGF-β during cancer cachexia disrupt mitochondrial homeostasis leading to dysfunction mitochondria. Dysfunctional mitochondria release aberrant amounts of reactive oxygen species (ROS) and decrease ATP production. This leads to chronic activation of AMPK to negatively regulate protein synthesis causing decreased muscle mass. The figure was made with Servier Medical Art (http://www.servier.com/Powerpoint-image-bank).

Figure 3

Increased muscle use improves skeletal muscle mitochondrial homeostasis in healthy and cachectic conditions. Sedentary behavior or muscle disuse is associated with decreased mitochondrial biogenesis, improper balance of mitochondrial dynamics, dysregulation of autophagy, and mitochondrial dysfunction. Increasing muscle use by reducing sedentary behavior or exercise will increase mitochondrial biogenesis, regulate mitochondrial dynamics, improve autophagic flux, and improve mitochondrial function and ATP efficiency. Overall increased muscle use will lead to skeletal muscle mitochondrial and metabolic homeostasis. The figure was made with Servier Medical Art (http://www.servier.com/Powerpoint-image-bank).