Mitochondrial adaptations in thermogenic tissues during cancer cachexia and upon different ambient temperatures

Mitochondrial dysfunction is an emerging hallmark of cancer cachexia (CC), which is a detrimental muscle-wasting condition that affects 50-80% of patients with metastatic cancer. Despite its high prevalence, little is known about the molecular triggers of CC, possibly because the current preclinical models does not fully recapitulate the human condition of CC. Specifically there is a lack of translatable evidence on the mechanisms leading to mitochondrial dysfunction in skeletal muscle and adipose tissues in the context of CC. Standard housing temperature (ST), which imposes cold-stress on mice, is a key disregarded factor that has a major impact on the functionality of thermogenic tissues, including skeletal muscle (SkM) and brown adipose tissue (BAT). Thermoneutral (TN) housing is an emerging approach to better recapitulate the human condition in preclinical models of, for example, obesity, type 2 diabetes and atherosclerosis. However, whether thermoneutral housing leads to an improved recapitulation of human CC and/or alters mitochondrial biology during CC is unknown. In this study, we show for the first time that glucose tolerance was improved in colon (C26) tumor-bearing cachectic mice housed at TN, in contrast to a worsening of glucose tolerance in TBM housed at ST. This was independent of relevant metabolic circulating factors such as leptin, FGF21 and GDF15. Muscle and fat mass, as well as molecular signatures of atrophy, were similarly affected in both housing temperatures. Maximal oxygen consumption was increased in SkM (23%) and BAT (47%) of cachectic mice housed at ST. Remarkably, TN housing completely blunted this effect. Interestingly, all cachectic mice showed decreased total ATP levels in both BAT and SkM, independent of the housing temperature. Assessment of gene expression of uncoupling proteins (Ucps) showed that Ucp2 was decreased only in BATs of cachectic mice at ST, whereas an increase was observed in SkM of cachectic mice housed at either temperature. Ucp2 has been reported to have a role on glucose metabolism, calcium homeostasis and ATP production. Thus, we propose that during CC, a differential modulation of Ucp2 expression could be responsible for the altered bioenergetics in BAT and SkM, and the mechanisms underlying differ depending on the ambient temperature. Ongoing work is being directed towards further assessing this hypothesis and validating whether the operating molecular signals occurring in TN better mimic human CC.