Hepatic mitochondrial adaptations to physical activity: impact of sexual dimorphism, PGC1α and BNIP3‐mediated mitophagy

Abstract

Hepatic mitochondrial adaptations to physical activity may be regulated by biogenesis- and mitophagy-associated pathways in a sex-dependent manner. Here, we tested if mice with targeted deficiencies in liver-specific peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α; LPGC1α ) and BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3)-mediated mitophagy (BNIP3 ) would have reduced physical activity-induced adaptations in respiratory capacity, H O emission and mitophagy compared to wild-type (WT) controls and if these effects were impacted by sex. Male and female WT, LPGC1α and BNIP3 C57BL6/J mice were divided into groups that remained sedentary or had access to daily physical activity via voluntary wheel running (VWR) (n = 6-10/group) for 4 weeks. Mice had ad libitum access to low-fat diet and water. VWR reduced basal mitochondrial respiration, increased mitochondrial coupling and altered ubiquitin-mediated mitophagy in a sex-specific manner in WT mice. Female mice of all genotypes displayed higher electron transport system content, displayed increased ADP-stimulated respiration, produced less mitochondrially derived reactive oxygen species, exhibited reduced mitophagic flux, and were less responsive to VWR compared to males. Males responded more robustly to VWR-induced changes in hepatic mitochondrial function resulting in a match to adaptations found in females. Deficiencies in PGC1α and BNIP3 alone did not largely alter mitochondrial adaptations to VWR. However, VWR restored sex-dependent abnormalities in mitophagic flux in LPGC1α . Finally, BNIP3 mice had elevated mitochondrial content and increased mitochondrial respiration putatively through repressed mitophagic flux. In conclusion, hepatic mitochondrial adaptations to physical activity are more dependent on sex than PGC1α and BNIP3.

Mst1 inhibition attenuates non-alcoholic fatty liver disease via reversing Parkin-related mitophagy

“…Many researchers have attempted to demonstrate the protective role played by mitophagy in attenuating fatty liver disease [9], [41]. However, there have been no studies investigating the upstream regulatory mechanisms for mitophagy management in the progression of NAFLD.…”

Breast cancer endocrine therapy exhausts adipocyte progenitors promoting weight gain and glucose intolerance

“…For all other complexes, neither TAM nor EWD treatment impacted protein content in either diet group (Supplemental Fig 3G-H). These data suggest that the liver phenotype observed in HFHS mice treated with TAM or EWD is not the product of direct action of TAM or EWD on hepatic mitochondria after 7 weeks of treatment; however, disruption of ER signaling is known to directly impact the liver in several studies 48,49 .…”

Sex differences in the regulation of hepatic mitochondrial turnover following physical activity: do males need more quality control than females?

“…To address these uncertainties, in a study published in the current issue of The Journal of Physiology , Von Schulze et al . () compared hepatic mitochondrial responses to 4 weeks of voluntary wheel running in male and female mice. Rather than focusing on hepatic steatosis per se , they recognized the importance of first establishing the fundamental mechanisms regulating hepatic mitochondrial turnover in the absence of disease.…”

“…Given that the risk for developing NAFLD may differ between sexes, investigating the sex-specific relationship between mitochondrial function and exercise adaptations could lead to new understandings of how sedentarism increases lipid stress on the liver. To address these uncertainties, in a study published in the current issue of The Journal of Physiology, Von Schulze et al (2018) compared hepatic mitochondrial responses to 4 weeks of voluntary wheel running in male and female mice. Rather than focusing on hepatic steatosis per se, they recognized the importance of first establishing the fundamental mechanisms regulating hepatic mitochondrial turnover in the absence of disease.…”

“…The investigation by Von Schulze et al . () highlights the critical importance of comparing sex differences in studies. To this end, the study suggests that physical activity is essential for males to maintain mitochondrial integrity in conjunction with more coupled respiration like females, even though their bioenergetic capacities may remain lower than females.…”