Mitochondrial Dysfunction in Cancer Cachexia: Impact on Muscle Health and Regeneration

Abstract

Cancer cachexia is a frequently neglected debilitating syndrome that, beyond representing a primary cause of death and cancer therapy failure, negatively impacts on patients' quality of life. Given the complexity of its multisystemic pathogenesis, affecting several organs beyond the skeletal muscle, defining an effective therapeutic approach has failed so far. Revamped attention of the scientific community working on cancer cachexia has focused on mitochondrial alterations occurring in the skeletal muscle as potential triggers of the complex metabolic derangements, eventually leading to hypercatabolism and tissue wasting. Mitochondrial dysfunction may be simplistically viewed as a cause of energy failure, thus inducing protein catabolism as a compensatory mechanism; however, other peculiar cachexia features may depend on mitochondria. On the one side, chemotherapy also impacts on muscle mitochondrial function while, on the other side, muscle-impaired regeneration may result from insufficient energy production from damaged mitochondria. Boosting mitochondrial function could thus improve the energetic status and chemotherapy tolerance, and relieve the myogenic process in cancer cachexia. In the present work, a focused review of the available literature on mitochondrial dysfunction in cancer cachexia is presented along with preliminary data dissecting the potential role of stimulating mitochondrial biogenesis via PGC-1α overexpression in distinct aspects of cancer-induced muscle wasting.

Keywords: PGC-1α; cancer cachexia; metabolism; mitochondria; muscle wasting; myogenesis; regeneration.

Figure A1

(A) Body weight change during tumor growth and chemotherapy experimental period of 14- and 22-month-old WT (n = 5; 7) and MCK-PGC-1α mice (n = 5; 5) bearing the LLC tumor. Data are reported as % ± SD of the initial body weight (IBW); (B) Gastrocnemius (GSN), heart, and epididymal white adipose tissue (eWAT) weight; data are expressed in mg ± SD; (C) Voluntary grasping strength; data (means ± SD) expressed in Newton. (D) Hematocrit. Data (means ± SD) expressed as percentages of total blood. For all panels, the significance of the differences was assessed by Student’s t-test for independent samples: * p < 0.05, ** p < 0.01, *** p < 0.001 vs. LLC DOX WT.

Figure 1

Mitochondria-targeted anti-cachexia interventions. Interventions focused on mitochondria to improve cancer and chemotherapy-induced muscle wasting may include the modulation of mitochondrial biogenesis, dynamics (fusion and fission), and mitophagy. Different strategies have been adopted to directly target mitochondria: SS-31 protects cardiolipin, enhancing mitochondrial activity and energy production through increased electron transport chain (ETC) efficiency; trimetazidine (TMZ) inhibits the 3-ketoacyl-CoA thiolase (KAT) activity, shifting the mitochondrial metabolism towards oxidative respiration and increasing mitochondrial function; the genetic deletion of pyruvate dehydrogenase kinase 4 (PDK4) enhances the influx of pyruvate into the TCA cycle, likely improving mitochondrial homeostasis. Image created with BioRender.com (accessed on 17 August 2021).

Figure 2

Cancer and the consequent inactivity impair the myogenic process, either directly via cytokine release or through several mechanisms including neuromuscular junction (NMJ) disruption, and mitochondrial and sarcolemmal damage. Several interventions have been proposed, mainly focused on signaling pathway inhibition, cytokine modulation, and exercise or exercise-mimicking metabolism modulators. Image created with BioRender.com (accessed on 17 August 2021).

Figure 3

(A,B) Representative Western blotting bands and densitometric analysis of PGC-1α protein expression, normalized by GAPDH. Data are reported as % ± SD of the uninjured control group; (C,D) Representative H&E panels and CSA quantification of injured muscles of either healthy or cachectic WT and MCK-PGC-1α mice. Data are expressed as % ± SD of the uninjured WT control group; (E) Representative pictures of tibialis anterior muscles according to its specific experimental condition. (F) Representative Western blotting bands and densitometric analysis of cyt c protein, normalized by GAPDH expression. Data are reported as % ± SD of uninjured muscle in each experimental condition. For all panels, the significance of the differences was assessed by Student’s t-test for independent samples: * p < 0.05, *** p < 0.001.

Figure 4

Proposed schematic pathogenesis of muscle wasting in cancer cachexia according to primary, antagonistic, and integrative hallmarks. Image created with BioRender.com (accessed on 17 August 2021).