High-fat diet (HFD) plays a central role in the initiation of mitochondrial dysfunction that significantly contributes to skeletal muscle metabolic disorders in obesity. However, the mechanism by which HFD weakens skeletal muscle metabolism by altering mitochondrial function and biogenesis is unknown. Given the emerging roles of microRNAs (miRNAs) in the regulation of skeletal muscle metabolism, we sought to determine whether activation of a specific miRNA pathway would rescue the HFD-induced mitochondrial dysfunction via the sirtuin-1 (SIRT-1)/ peroxisome proliferator–activated receptor γ coactivator-1α (PGC-1α) pathway, a pathway that governs genes necessary for mitochondrial function. We here report that miR-149 strongly controls SIRT-1 expression and activity. Interestingly, miR-149 inhibits poly(ADP-ribose) polymerase-2 (PARP-2) and so increased cellular NAD⁺ levels and SIRT-1 activity that subsequently increases mitochondrial function and biogenesis via PGC-1α activation. In addition, skeletal muscles from HFD-fed obese mice exhibit low levels of miR-149 and high levels of PARP-2, and they show reduced mitochondrial function and biogenesis due to a decreased activation of the SIRT-1/PGC-1α pathway, suggesting that mitochondrial dysfunction in the skeletal muscle of obese mice may be because of, at least in part, miR-149 dysregulation. Overall, miR-149 may be therapeutically useful for treating HFD-induced skeletal muscle metabolic disorders in such pathophysiological conditions as obesity and type 2 diabetes.

Skeletal muscle aging is associated with increased inflammation and oxidative stress, a decrease in the ability to rebuild muscle after injury and in response to exercise. In this perspective, we discuss the mechanisms regulating Sirt1 activity and expression in skeletal muscles, emphasizing their implications in muscle physiology and the impairment of muscle function with age.

Mechanical loading of muscles by intrinsic muscle activity or passive stretch leads to an increase in the production of reactive oxygen species. The NAD-dependent protein deacetylase SIRT1 is involved in the protection against oxidative stress by enhancing FOXO-driven Sod2 transcription. In this report, we unravel a mechanism triggered by mechanical stretch of skeletal muscle cells that leads to an EGR1-dependent transcriptional activation of the Sirt1 gene. The resulting transient increase in SIRT1 expression generates an antioxidative response that contributes to reactive oxygen species scavenging.

Obesity is a common comorbidity of chronic obstructive pulmonary disease (COPD) and has been associated with worse outcomes. However, it is unknown whether the interaction between obesity and COPD modulates diaphragm shape and consequently its function. The body mass index (BMI) has been used as a correlate of obesity. We tested the hypothesis that the shape of the diaphragm muscle and size of the ring of its insertion in non-COPD and COPD subjects are modulated by BMI. We recruited 48 COPD patients with postbronchiodilator forced expiratory volume in 1 s (FEV1)-to-forced vital capacity (FVC) < 0.7 and 29 age-matched smoker/exsmoker control (non-COPD) subjects, who underwent chest computed tomography (CT) at lung volumes ranging from functional residual capacity (FRC) to total lung capacity (TLC). We then computed maximum principal diaphragm curvature in the midcostal region of the left hemidiaphragm at the end of inspiration during quiet breathing (EI) and at TLC. The radius of maximum curvature of diaphragm muscle increased with BMI in both COPD and non-COPD subjects. The size of diaphragm ring of insertion on the chest wall also increased significantly with increasing BMI. Surprisingly, COPD severity did not appear to cause significant alteration in diaphragm shape except in normal-weight subjects at TLC. Our data uncovered important factors such as BMI, the size of the diaphragm ring of insertion, and disease severity that modulate the structure of the ventilatory pump in non-COPD and COPD subjects.

A complex rearrangement mutation in the mouse titin gene leads to an in-frame 83-amino acid deletion in the N2A region of titin. Autosomal recessive inheritance of the titin muscular dystrophy with myositis ( Ttn ^mdm/mdm) mutation leads to a severe early-onset muscular dystrophy and premature death. We hypothesized that the N2A deletion would negatively impact the force-generating capacity and passive mechanical properties of the mdm diaphragm. We measured in vitro active isometric contractile and passive length-tension properties to assess muscle function at 2 and 6 wk of age. Micro-CT, myosin heavy chain Western blotting, and histology were used to assess diaphragm structure. Marked chest wall distortions began at 2 wk and progressively worsened until 5 wk. The percentage of myofibers with centrally located nuclei in mdm mice was significantly ( P < 0.01) increased at 2 and 6 wk by 4% and 17%, respectively, compared with controls. At 6 wk, mdm diaphragm twitch stress was significantly ( P < 0.01) reduced by 71%, time to peak twitch was significantly ( P < 0.05) reduced by 52%, and half-relaxation time was significantly ( P < 0.05) reduced by 57%. Isometric tetanic stress was significantly ( P < 0.05) depressed in 2- and 6-wk mdm diaphragms by as much as 64%. Length-tension relationships of the 2- and 6-wk mdm diaphragms showed significantly ( P < 0.05) decreased extensibility and increased stiffness. Slow myosin heavy chain expression was aberrantly favored in the mdm diaphragm at 6 wk. Our data strongly support early contractile and passive mechanical aberrations of the respiratory pump in mdm mice.