Females and males have unique characteristics that effect skeletal muscle's microenvironment and intrinsic signaling. These differences provide a strong rationale for distinct causes for cancer cachexia development and treatment in males and females.

Doxorubicin (DOX) is a highly effective antineoplastic agent used in cancer treatment. Unfortunately, clinical use of DOX is limited due to the development of dose-dependent toxicity to cardiac and respiratory (i.e., diaphragm) muscles. After administration, DOX preferentially localizes to the inner mitochondrial membrane, where it promotes cellular toxicity via enhanced mitochondrial reactive oxygen species (ROS) production. Although recent evidence suggests that amelioration of mitochondrial ROS emission preserves cardiorespiratory muscle function following DOX treatment, the mechanisms responsible for this protection remain unknown. Therefore, we tested the hypothesis that DOX-induced mitochondrial ROS production is required to stimulate pathological signaling by the autophagy/lysosomal system (ALS), the ubiquitin-proteasome pathway (UPP), and the unfolded protein response (UPR). Cause and effect were determined by administration of the mitochondria-targeted peptide SS-31 to DOX-treated animals. Interestingly, while SS-31 abrogated aberrant ROS emission in cardiorespiratory muscles of DOX-treated animals, our results revealed muscle-specific regulation of effector pathways. In the heart, SS-31 prevented DOX-induced proteolytic signaling through the ALS and UPP. In contrast, ALS signaling was inhibited by SS-31 in the diaphragm, but the UPP was not affected. UPR signaling was activated in both muscles at eukaryotic translation initiation factor 2α (eIF2α) S51 in the heart and diaphragm of DOX-treated animals and was attenuated with SS-31 treatment in both tissues. However, downstream signaling of eIF2α (activating transcription factor 4 and CCAAT/enhancer-binding protein homologous protein) was diminished in the heart but upregulated in the diaphragm with DOX. Collectively, these results show that DOX-induced ROS production plays distinct roles in the regulation of cardiac and diaphragm muscle proteolysis.

Skeletal muscle has the dynamic capability to modulate protein turnover in response to anabolic stimuli, such as feeding and contraction. We propose that anabolic resistance, the suppressed ability to induce protein synthesis, is central to cancer-induced muscle wasting. Furthermore, we propose that resistance exercise training has the potential to attenuate or treat cancer-induced anabolic resistance through improvements in oxidative metabolism.

New Findings What is the central question of this study?Interleukin‐6 has been associated with muscle mass and metabolism in both physiological and pathological conditions. A causal role for interleukin‐6 in the induction of fatigue and disruption of mitochondrial function has not been determined. What is the main finding and its importance?We demonstrate that chronically elevated interleukin‐6 increased skeletal muscle fatigability and disrupted mitochondrial content and function independent of changes in fibre type and mass. Abstract Interleukin‐6 (IL‐6) can initiate intracellular signalling in skeletal muscle by binding to the IL‐6‐receptor and interacting with the transmembrane gp130 protein. Circulating IL‐6 has established effects on skeletal muscle mass and metabolism in both physiological and pathological conditions. However, the effects of circulating IL‐6 on skeletal muscle function are not well understood. The purpose of this study was to determine whether chronically elevated systemic IL‐6 was sufficient to disrupt skeletal muscle force, fatigue and mitochondrial function. Additionally, we examined the role of muscle gp130 signalling during overexpression of IL‐6. Systemic IL‐6 overexpression for 2 weeks was achieved by electroporation of an IL‐6 overexpression plasmid or empty vector into the quadriceps of either C57BL/6 (WT) or skeletal muscle gp130 knockout (KO) male mice. Tibialis anterior muscle in situ functional properties and mitochondrial respiration were determined. Interleukin‐6 accelerated in situ skeletal muscle fatigue in the WT, with a 18.5% reduction in force within 90 s of repeated submaximal contractions and a 7% reduction in maximal tetanic force after 5 min. There was no difference between fatigue in the KO and KO+IL‐6. Interleukin‐6 reduced WT muscle mitochondrial respiratory control ratio by 36% and cytochrome c oxidase activity by 42%. Interleukin‐6 had no effect on either KO respiratory control ratio or cytochrome c oxidase activity. Interleukin‐6 also had no effect on body weight, muscle mass or tetanic force in either genotype. These results provide evidence that 2 weeks of elevated systemic IL‐6 is sufficient to increase skeletal muscle fatigability and decrease muscle mitochondrial content and function, and these effects require muscle gp130 signalling.

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.