Muscle weakness precedes atrophy during cancer cachexia and is linked to muscle-specific mitochondrial stress

Abstract

Muscle weakness and wasting are defining features of cancer-induced cachexia. Mitochondrial stress occurs before atrophy in certain muscles, but the possibility of heterogeneous responses between muscles and across time remains unclear. Using mice inoculated with Colon-26 (C26) cancer, we demonstrate that specific force production was reduced in quadriceps and diaphragm at 2 weeks in the absence of atrophy. At this time, pyruvate-supported mitochondrial respiration was lower in quadriceps while mitochondrial H2O2 emission was elevated in diaphragm. By 4 weeks, atrophy occurred in both muscles, but specific force production increased to control levels in quadriceps such that reductions in absolute force were due entirely to atrophy. Specific force production remained reduced in diaphragm. Mitochondrial respiration increased and H2O2 emission was unchanged in both muscles vs control while mitochondrial creatine sensitivity was reduced in quadriceps. These findings indicate muscle weakness precedes atrophy and is linked to heterogeneous mitochondrial alterations that could involve adaptive responses to metabolic stress.Eventual muscle-specific restorations in specific force and bioenergetics highlight how the effects of cancer on one muscle do not predict the response in another muscle. Exploring heterogeneous responses of muscle to cancer may reveal new mechanisms underlying distinct sensitivities, or resistance, to cancer cachexia.

Lipid hydroperoxides promote sarcopenia through carbonyl stress

“…As described in the previous paragraph, aging promoted muscle weakness prior to atrophy. Similarly, muscle atrophy induced by cancer cachexia is also preceded by muscle weakness [34]. Thus, these observations highlight the need to better study the mechanisms that regulate force-generating capacity independent of muscle mass.…”

Cardiac atrophy, dysfunction, and metabolic impairments: a cancer-induced heart failure phenotype

“…Skeletal muscle atrophy is driven by upregulation of UPS-mediated protein degradation. 8 However, Murf1 and Atrogin-1 , muscle-specific E3 ubiquitin ligases, did not increase in hearts of ovarian tumor-bearing mice (Figure 5G), suggesting that UPS-mediated protein degradation does not play a significant role in the development of cardiac atrophy with ovarian cancer.…”

“…6,7 Skeletal muscle weakness and atrophy are well-known consequences of cancer cachexia. 8 Muscle wasting is attributed to a decline in protein synthesis and an increase in degradation, mediated by systemic increases in inflammatory cytokines released by activated immune cells of the tumor and host. 9 These cytokines promote hyperactivation of ubiquitin-proteasome system (UPS)-mediated protein degradation, leading to the breakdown of myofibrillar proteins and muscle atrophy.…”

“…14,15 We also determined whether cancer perturbed cardiac substrate metabolism and increased oxidative stress levels in the myocardium, given such stress responses have been reported in skeletal muscle during cancer. 8,16,17 To investigate the underlying mechanisms of cancer-induced cardiac impairments, we quantified the cardiac gene program and catabolic pathways that regulate protein degradation in the heart. We show that cancer causes cardiac atrophy, dysfunction, metabolic dysregulation, and exercise intolerance.…”

Lipid hydroperoxides promote sarcopenia through carbonyl stress

“…As described in the previous paragraph, aging promoted muscle weakness prior to atrophy. Similarly, muscle atrophy induced by cancer cachexia is also preceded by muscle weakness ( Delfinis et al, 2022 ). Thus, these observations highlight the need to better study the mechanisms that regulate force-generating capacity independent of muscle mass.…”