Skeletal Muscle Mitochondrial Function in High‐Fat Diet Fed Mice with Genetically Modified Myostatin Expression
Authors: Khamoui Andy V. , Abraham Andrea , Reisz‐Porszasz Suzanne , Rossiter Harry B. 
Published: November 2023

RationaleMyostatin (Mstn) is a transforming growth factor‐β superfamily member that contributes to regulation of skeletal muscle mass. Myostatin also has a role in regulating metabolism: knockout reduces capacity for mitochondrial oxidative phosphorylation (OXPHOS), while overexpression increases the proportion of mitochondria‐rich oxidative fibers. Consumption of a high‐fat diet (HF) adversely affects human health by inducing metabolic disease and mitochondrial dysfunction in skeletal muscle. What has not been well‐established is if the oxidative features generated by transgenic overexpression of Mstn protects against HF. This study aimed to determine whether muscle‐specific overexpression of myostatin ameliorates the deleterious effects of HF on mitochondrial function.MethodsOne year old male mice with constitutive genetic modification of Mstn expression (KO, knock‐out; TG, transgenic overexpression) were kept on HF for 4 weeks (KO‐HF, TG‐HF, n=6/group). Age‐matched wild type mice (WT) were fed a regular diet (WT‐RG, n=8) or HF (WT‐HF, n=7). Fiber bundles from the medial gastrocnemius were saponin‐permeabilized and mitochondrial function measured by high‐resolution respirometry. LEAK (non‐phosphorylating O2 flux with saturating malate+palmitoylcarnitine), OXPHOS capacity (O2 flux with saturating complex I+II substrates), and electron transport system capacity (ETS; maximal uncoupled O2 flux with FCCP) were measured.ResultsOXPHOS capacity tended to be greater in WT‐HF vs. WT‐RG (66±21 vs. 54±7 pmol/s/mg, p=0.12). ETS capacity was significantly greater in WT‐HF vs. WT‐RG (86±23 vs. 65±11 pmol/s/mg, p<0.05). LEAK was greater in KO‐HF and TG‐HF, vs. WT‐HF (p<0.05). OXPHOS and ETS capacity were significantly lower (~40%) in both KO‐HF and TG‐HF vs. WT‐HF (p<0.05), and not different from WT‐RG (p>0.05). The coupling control ratio (OXPHOS/ETS) in KO‐HF was greater (1.03±0.17, p<0.05) than all other groups (TG‐HF 0.77±0.09, WT‐HF 0.79±0.11, WT‐RG 0.83±0.08, p>0.05). Flux control ratio for complex I was lower in KO‐HF (0.49±0.08) and greater in TG‐HF (0.65±0.08) when compared to WT‐HF (0.56±0.03, p<0.05).ConclusionsMitochondrial respiration increased following HF, a possible compensatory response to increased reactive oxygen species. Interestingly, myostatin knockout and overexpression each decreased absolute muscle OXPHOS and ETS capacity to that of WT‐RG, which indicates an attenuated mitochondrial adaptation to the HF diet insult. With increasing uncoupling, OXPHOS approaches ETS; therefore the increased coupling control ratio for KO‐HF may reflect increased energy expenditure not available for oxidative phosphorylation. The preserved coupling and complex I control ratios for TG‐HF may therefore indicate a better maintenance of phosphorylation efficiency in the face of the HF diet. Whether myostatin overexpression can protect against the deleterious effects of a high fat diet deserves further investigation.Support or Funding InformationNIH/NIGMS SC1GM089648 and Pulmonary Education and Research Foundation