Altering aspects of mitochondrial quality to improve musculoskeletal outcomes in disuse atrophy

• Published in: Journal of applied physiology (1985) Vol. 129; no. 6; pp. 1290 - 1303
• Main Authors: Rosa-Caldwell, Megan E, Lim, Seongkyun, Haynie, Wesley S, Jansen, Lisa T, Westervelt, Lauren C, Amos, Madeline G, Washington, Tyrone A, Greene, Nicholas P
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.12.2020
• Subjects: Animal tissues; Atrophy; Catalase; Females; Mitochondria; mRNA; Muscles; Prognosis; Proteasomes; Protein turnover; Proteins; Quality control; Rodents; Ubiquitin; muscle atrophy; PGC1α; females; mitochondria; catalase
• DOI: 10.1152/JAPPLPHYSIOL.00407.2020
• ISSN: 8750-7587

Muscle atrophy is a significant moderator for disease prognosis; as such, interventions to mitigate disuse-induced muscle loss are imperative to improve clinical interventions. Mitochondrial deteriorations may underlie disuse-induced myopathies; therefore, improving mitochondrial quality may be an enticing therapeutic intervention. However, different mitochondria-based treatments may have divergent impacts on the prognosis of disuse atrophy. Therefore, the purpose of this study was to investigate different mitochondria-centered interventions during disuse atrophy in hindlimb unloaded male and female mice. Male and female mice overexpressing peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) or mitochondrially targeted catalase (MCAT) and their respective wild-type (WT) littermate controls were hindlimb unloaded for 7 days to induce disuse atrophy or allowed normal ambulatory activity (cage control; CON). After designated interventions, animals were euthanized, and tissues were collected for measures of mitochondrial quality control and protein turnover. Although PGC-1α overexpression mitigated ubiquitin-proteasome activation ( and mRNA content), this did not correspond to phenotypic protections from disuse-induced atrophy. Rather, PGC-1α mice appeared to have a greater reliance on autophagic protein breakdown compared with WT mice. In MCAT mice, females exhibited a mitigated response to disuse atrophy; however, this effect was not noted in males. Despite these phenotypic differences, there were no clear cellular signaling differences between MCAT hindlimb unloaded females and MCAT fully loaded females. PGC-1α overexpression does not protect against phenotypic alterations during disuse atrophy but appears to shift catabolic pathways moderating atrophy. However, increased mitochondrially targeted catalase activity appears to blunt disuse atrophy within highly oxidative muscles specifically in female mice. We present data suggesting that mitochondria-based interventions may mitigate disuse atrophy. However, the efficacy of mitochondria-based interventions may vary depending on the specific target of the intervention and the sex of the organism. Females appear to be more responsive to increased mitochondrial catalase as a potential therapeutic for mitigating disuse atrophy.