TFAM overexpression diminishes skeletal muscle atrophy after hindlimb suspension in mice

Abstract

The present study aims to investigate if overexpressing the mitochondrial transcription factor A (TFAM) gene in a transgenic mouse model diminishes soleus and gastrocnemius atrophy occurring during hindlimb suspension (HLS). Additionally, we aim to observe if combining exercise training in TFAM transgenic mice prior to HLS has a synergistic effect in preventing skeletal muscle atrophy. Male C57BL/6J-based transgenic mice (12-14 weeks old) overexpressing TFAM were assigned to a control (T-Control), 7-day HLS (T-HLS), and 2-week exercise training prior to 7-day HLS (T-Ex+HLS) groups. These groups were compared to male C57BL/6J wildtype (WT) mice (12-14 weeks old) assigned to Control, 7-day HLS (HLS), 2week exercise training prior to 7-day HLS (Ex+HLS), and 2-week exercise training (Ex). Overexpressing TFAM results in a decrease of 8.3% in soleus and 2.6% in gastrocnemius muscle weight to bodyweight ratio after only HLS compared to wild-type mice incurring a loss of 27.1% in soleus and 21.5% in gastrocnemius muscle after HLS. Our data indicates TFAM may play a critical role in protecting skeletal muscle from disuse atrophy and is correlated with increased expression of antioxidants (SOD-2) and potential redox balance. TFAM may be an attractive molecule of interest for potential, future therapeutic development.

Bioactive Components in Whole Grains for the Regulation of Skeletal Muscle Function

“…SIRT2 is reported to modulate skeletal muscle atrophy by inhibiting excessive autophagy [ 27 ] and improve myotube differentiation and hypertrophy [ 28 ]. Enhanced mitochondrial function is conducive to improving muscle atrophy [ 29 ], while the reduction of mitochondrial biogenesis and oxidative phosphorylation leads to the production of ROS, which causes excessive muscle protein degradation [ 30 ]. Mitochondrial transcription factor A (TFAM) binds and coats mtDNA, protecting it from ROS-induced degradation and maintaining mitochondrial function [ 26 ].…”

5-Heptadecylresorcinol Ameliorates Obesity-Associated Skeletal Muscle Mitochondrial Dysfunction through SIRT3-Mediated Mitophagy

“…As the enzymes of the mitochondrial electron transport chain, Complex II and Complex IV participate in the production of the vast majority of cellular energy. In addition, TFAM is involved in mitochondrial biogenesis which is activated by PGC-1α and coats mtDNA, protecting against ROS exposure. , The overexpression of TFAM could alleviate aging and obesity-induced muscle atrophy . Here, we found that the decreased expression of TFAM, Complex II, and Complex IV caused by obesity was upregulated by AR-C17 administration in both PA-induced C2C12 cells and obese mice.…”

“…Activation of mitophagy is proven to improve mitochondrial function in skeletal muscle . Inhibition of mitophagy proteins such as Beclin-1, P62, and LC3 could affect the production of lysosomes, which generate the small molecules reutilized by cells to produce new healthy mitochondria. , According to recent studies, poor autophagy flux and downregulated level of mitophagy-related proteins such as Beclin-1 and P62 are detected in aging skeletal muscle . In addition, knockdown of Parkin causes damaged mitochondrial quality and decreased mtDNA number and oxidative phosphorylation level, while overexpression of Parkin improves muscle mass and exercise capacity in atrophied skeletal muscle .…”

Mitochondrial Dysfunction in Intensive Care Unit-Acquired Weakness and Critical Illness Myopathy: A Narrative Review

“…Reductions in or complete abolishment of TFAM have been associated with marked decreases in mtDNA, leading to profound skeletal muscle wasting [ 163 ]. The important role of TFAM in preservation of muscle mass is underlined by the fact that TFAM overexpression has been shown to protect from hindlimb suspension-induced muscle wasting [ 164 ]. In contrast, in survivors of critical illness, an upregulation in the mRNA of PGC1α, NRF1 and TFAM could be indicative of ongoing repairing processes or, on the other hand, could serve as a mechanism of resilience [ 82 ].…”