Linking Cancer Cachexia-Induced Anabolic Resistance to Skeletal Muscle Oxidative Metabolism

Abstract

Cancer cachexia, a wasting syndrome characterized by skeletal muscle depletion, contributes to increased patient morbidity and mortality. While the intricate balance between protein synthesis and breakdown regulates skeletal muscle mass, the suppression of basal protein synthesis may not account for the severe wasting induced by cancer. Therefore, recent research has shifted to the regulation of “anabolic resistance,” which is the impaired ability of nutrition and exercise to stimulate protein synthesis. Emerging evidence suggests that oxidative metabolism can regulate both basal and induced muscle protein synthesis. While disrupted protein turnover and oxidative metabolism in cachectic muscle have been examined independently, evidence suggests a linkage between these processes for the regulation of cancer-induced wasting. The primary objective of this review is to highlight the connection between dysfunctional oxidative metabolism and cancer-induced anabolic resistance in skeletal muscle. First, we review oxidative metabolism regulation of muscle protein synthesis. Second, we describe cancer-induced alterations in the response to an anabolic stimulus. Finally, we review a role for exercise to inhibit cancer-induced anabolic suppression and mitochondrial dysfunction.

Systemic Actions of Breast Cancer Facilitate Functional Limitations

“…Cachexia, myopenia, and functional limitations in cancer patients are generally associated with a negative energy balance resulting from either reduced energy production or increased energy expenditure during disease progression [102][103][104]. Advanced cancer patients have enhanced thermogenesis that increases energy expenditure, which is consistent with the observation in cachectic tumor-bearing animals [105].…”

Leucine-Rich Diet Modulates the Metabolomic and Proteomic Profile of Skeletal Muscle during Cancer Cachexia

“…Mitochondria is the central energy-generating organelle in eukaryotic cells, and their imbalances cause profound changes to cells, especially to glycolytic pathway performance changing the whole cellular function [ 16 , 17 ]. Recent studies have shown that mitochondria are an essential framework for understanding the cachexia process [ 18 ], highlighting that during cancer-cachexia, there is both an imbalance in skeletal muscle mitochondrial biogenesis [ 18 ] and an increase in mitochondrial apoptosis [ 19 ].…”

Resistance Exercise’s Ability to Reverse Cancer-Induced Anabolic Resistance

“…The inability to stimulate protein synthesis in response to anabolic stimuli, termed anabolic resistance, has been observed in aging and wasting conditions (5–7). Furthermore, disrupted proteostasis and oxidative metabolism are well-described in cachectic muscle (8–10). However, the mechanisms of cancer-induced anabolic resistance are not thoroughly understood.…”