Little is known about the association between sarcopenia and cardiovascular disease (CVD) among middle-aged and older adults. Using the nationally representative data from the China Health and Retirement Longitudinal Study (CHARLS), we conducted cross-sectional and longitudinal analyses to investigate the association between sarcopenia status and CVD in middle-aged and older Chinese population. The sample comprised 15,137 participants aged at least 45 years from the CHARLS 2015. Sarcopenia status was defined according to the Asian Working Group for Sarcopenia 2019 (AWGS 2019) criteria. CVD was defined as the presence of physician-diagnosed heart disease and/or stroke. A total of 11,863 participants without CVD were recruited from the CHARLS 2015 and were followed up in 2018. Cox proportional hazards regression models were conducted to examine the effect of sarcopenia on CVD. The pre valence of CVD in total populations, no-sarcopenia, possible sarcopenia and sarcopenia individuals were 12.6% (1905/15,137), 10.0% (1026/10,280), 18.1% (668/3685), 18.0% (211/1172), respectively. Both possible sarcopenia [OR (95% CI): 1.29 (1.13–1.48)] and sarcopenia [1.72 (1.40–2.10)] were associated with CVD in total populations. During the 3.6 years of follow-up, 1,273 cases (10.7%) with incident CVD were identified. In the longitudinal analysis, individuals with the diagnosis of possible sarcopenia (HR:1.22, 95% CI: 1.05–1.43) and sarcopenia participants (HR:1.33, 95% CI: 1.04–1.71) were more likely to have new onset CVD than no-sarcopenia peers. Both possible sarcopenia and sarcopenia, assessed using the AWGS 2019 criteria, were associated with higher CVD risk among middle-aged and older Chinese adults. None.

Recent studies have shown that FMS-like receptor tyrosine kinase 3 (Flt3) has a beneficial effect on cardiac maladaptive remodeling. However, the role and mechanism of Flt3 in mitochondrial dynamic imbalance under cardiac stress remains poorly understood. This study aims to investigate how Flt3 regulates p53-mediated optic atrophy 1 (OPA1) processing and mitochondrial fragmentation to improve cardiac remodeling. Mitochondrial fragmentation in cardiomyocytes was induced by isoprenaline (ISO) and H₂O₂ challenge, respectively, in vitro. Cardiac remodeling in mice was established by ligating the left anterior descending coronary artery or by chronic ISO challenge, respectively, in vivo. Our results demonstrated that the protein expression of acetylated-p53 (ac-p53) in mitochondria was significantly increased under cell stress conditions, facilitating the dissociation of PHB2-OPA1 complex by binding to prohibitin 2 (PHB2), a molecular chaperone that stabilizes OPA1 in mitochondria. This led to the degradation of the long isoform of OPA1 (L-OPA1) that facilitates mitochondrial fusion and resultant mitochondrial network fragmentation. This effect was abolished by a p53 K371R mutant that failed to bind to PHB2 and impeded the formation of the ac-p53-PHB2 complex. The activation of Flt3 significantly reduced ac-p53 expression in mitochondria via SIRT1, thereby hindering the formation of the ac-p53-PHB2 complex and potentiating the stability of the PHB2-OPA1 complex. This ultimately inhibits L-OPA1 processing and leads to the balancing of mitochondrial dynamics. These findings highlight a novel mechanism by which Flt3 activation mitigates mitochondrial fragmentation and dysfunction through the reduction of L-OPA1 processing by dampening the interaction between ac-p53 and PHB2 in cardiac maladaptive remodeling.

Cardiac surgery or transplant using cardioplegic arrest and cardiopulmonary bypass (CP/CPB) subjects the heart to mild reversible ischemic injury that results in pronounced myocardial stunning. Mitochondrial large conductance calcium-activated K⁺ channels (BK_Ca) in cardiomyocytes are potently cardioprotective and beneficially modulate respiration and ROS post-I/R injury. However, how BK_Ca-dependent K⁺ flux regulates ROS and respiration is unclear. We evaluated the BK_Ca activator rottlerin in a preclinical large animal pig CP/CPB model of myocardial stunning and evaluated BK_Ca-dependent cardioprotective mechanisms in vitro and in vivo. BK_Ca activation with the small molecule rottlerin significantly improved LV cardiac functional recovery and contractility at 1 h reperfusion. TEM showed larger mitochondria in the rottlerin group consistent with K⁺ influx. We also found that pigs with rottlerin treatment had increased electron transport chain supercomplexes (mSCs), which are thought to improve respiratory efficiency and reduce ROS. Consistent with increased mSC, rottlerin reduced ROS-dependent protein modification in CP/CPB pigs. In complementary studies, rottlerin and/or adenoviral overexpression of a mutant mito-BK_Ca increased respiration, altered mitochondrial morphology, increased mSC assembly, and significantly reduced ROS following in vitro CP/reoxygenation, similar to CP/CPB pigs. In summary, mito-BK_Ca activation increases mSCs and respiration while reducing ROS, suggesting that mSC-dependent improved respiratory efficiency promotes robust cardioprotection.

Mitochondrial dysfunction, including impaired respiration and increased reactive oxygen species (ROS), is an early feature of Alzheimer’s disease (AD) models. Electron transport chain supercomplexes (mSCs) regulate respiratory efficiency and ROS generation, yet genetic determinants of mSC organization in AD models remain underappreciated. Cox7a2l is known to promote CIII₂/CIV association and CIV incorporation into mSCs. We examined the commonly used mixed-background B6;129S 3xTg-AD mice and B6129SF2/J controls aged 12–15 months, as well as specific rat AD models for changes in mSC organization using blue and clear native-PAGE and DIA-MS. BN and CN-PAGE revealed a marked shift toward larger mSC assemblies in 3xTg-AD mice and a distinct ~650 kDa assembly of complex III absent from controls. Gene sequencing showed that 3xTg-AD mice retained the full-length Cox7a2l variant similar to 129S strains, whereas controls predominantly carried a shortened C57BL/6-associated variant. DIA-MS identified greatly increased Cox7a2l in differential mSC bands. Similar changes were found in 3xTg-AD heart tissue. In contrast, AD rat models and their controls, all expressing full-length Cox7a2l, did not exhibit comparable mSC differences. These findings suggest Cox7a2l genotype as a determinant of mSC organization and highlight the need to account for genetic background when interpreting mSC-dependent mitochondrial phenotypes in mixed-background 3xTg-AD studies. This distinction is essential for accurately separating strain-dependent effects from AD-associated mitochondrial changes.