Human Heart Failure Alters Mitochondria and Fiber 3D Structure Triggering Metabolic Shifts.

This study, utilizing SBF-SEM, reveals structural alterations in mitochondria and myofibrils in human heart failure (HF). Mitochondria in HF show changes in structure, while myofibrils exhibit increased cross-sectional area and branching. Metabolomic and lipidomic analyses indicate concomitant dysregulation in key pathways. The findings underscore the need for personalized treatments considering individualized structural changes in HF.

Trends in Racial, Ethnic, and Gender Diversity in Orthopaedic Surgery Adult Reconstruction Fellowships From 2007 to 2021.

BACKGROUND: Orthopaedic surgery has seen improvement in its representation of women, whereas the representation of racial/ethnic minorities has remained stagnant over the past decade. Overall, the surgical field lags behind other specialties in sex and racial/ethnic parity. Although demographic disparities within orthopaedics have been analyzed for both residents and faculty members, information for adult reconstruction fellows remains limited. METHODS: Sex and race/ethnicity demographics for adult reconstruction orthopaedic fellowship matriculants were collected via a database published by the Accreditation Council for Graduate Medical Education (ACGME) from 2007 to 2021. Statistical analyses, including descriptive statistics and significance testing, were performed. RESULTS: During the 14-year time frame, men trainees remained high with an overall average percentage of 88% and demonstrated increasing representation (P trend = .012). White non-Hispanics, Asians, Blacks, and Hispanics represented on average 54%, 11%, 3%, and 4%, respectively. White non-Hispanics (P trend = .039) and Asians (P trend = .030) saw increasing and decreasing representation, respectively. Women, Blacks, and Hispanics remained relatively stagnant throughout the observation period as no trends were appreciable (P trend >.05, each). CONCLUSION: Using publicly available demographic data from the Accreditation Council for Graduate Medical Education (ACGME) from 2007 to 2021, we found relatively limited progress in the representation of women and those from traditionally marginalized groups seeking additional training in adult reconstruction. Our findings mark an initial step in measuring the demographic diversity among adult reconstruction fellows. Further research is needed to ascertain specific factors likely to attract and retain members from minoritized groups into orthopaedics.

Identification of evolutionarily conserved regulators of muscle mitochondrial network organization.

Mitochondrial networks provide coordinated energy distribution throughout muscle cells. However, pathways specifying mitochondrial networks are incompletely understood and it is unclear how they might affect contractile fiber-type. Here, we show that natural energetic demands placed on Drosophila melanogaster muscles yield native cell-types among which contractile and mitochondrial network-types are regulated differentially. Proteomic analyses of indirect flight, jump, and leg muscles, together with muscles misexpressing known fiber-type specification factor salm, identified transcription factors H15 and cut as potential mitochondrial network regulators. We demonstrate H15 operates downstream of salm regulating flight muscle contractile and mitochondrial network-type. Conversely, H15 regulates mitochondrial network configuration but not contractile type in jump and leg muscles. Further, we find that cut regulates salm expression in flight muscles and mitochondrial network configuration in leg muscles. These data indicate cell type-specific regulation of muscle mitochondrial network organization through evolutionarily conserved transcription factors cut, salm, and H15.

Mitochondrial network configuration influences sarcomere and myosin filament structure in striated muscles.

Sustained muscle contraction occurs through interactions between actin and myosin filaments within sarcomeres and requires a constant supply of adenosine triphosphate (ATP) from nearby mitochondria. However, it remains unclear how different physical configurations between sarcomeres and mitochondria alter the energetic support for contractile function. Here, we show that sarcomere cross-sectional area (CSA) varies along its length in a cell type-dependent manner where the reduction in Z-disk CSA relative to the sarcomere center is closely coordinated with mitochondrial network configuration in flies, mice, and humans. Further, we find myosin filaments near the sarcomere periphery are curved relative to interior filaments with greater curvature for filaments near mitochondria compared to sarcoplasmic reticulum. Finally, we demonstrate variable myosin filament lattice spacing between filament ends and filament centers in a cell type-dependent manner. These data suggest both sarcomere structure and myofilament interactions are influenced by the location and orientation of mitochondria within muscle cells.

Three-dimensional remodelling of the cellular energy distribution system during postnatal heart development.

The heart meets the high energy demands of constant muscle contraction and calcium cycling primarily through the conversion of fatty acids into adenosine triphosphate (ATP) by a large volume of mitochondria. As such, the spatial relationships among lipid droplets (LDs), mitochondria, the sarcotubular system and the contractile apparatus are critical to the efficient distribution of energy within the cardiomyocyte. However, the connectivity among components of the cardiac cellular energy distribution system during postnatal development remains unclear. Here, we use volume electron microscopy to demonstrate that the sarcomere branches uniting the myofibrillar network occur more than twice as frequently during early postnatal development as in mature cardiomyocytes. Moreover, we show that the mitochondrial networks arranged in parallel to the contractile apparatus are composed of larger, more compact mitochondria with greater connectivity to adjacent mitochondria in mature as compared with early postnatal cardiomyocytes. Finally, we find that connectivity among mitochondria, LDs and the sarcotubular network is greater in developing than in mature muscles. These data suggest that physical connectivity among cellular structures may facilitate the communication needed to coordinate developmental processes within the cardiac muscle cell. This article is part of the theme issue 'The cardiomyocyte: new revelations on the interplay between architecture and function in growth, health, and disease'.

Regulation of the evolutionarily conserved muscle myofibrillar matrix by cell type dependent and independent mechanisms.

Skeletal muscles play a central role in human movement through forces transmitted by contraction of the sarcomere. We recently showed that mammalian sarcomeres are connected through frequent branches forming a singular, mesh-like myofibrillar matrix. However, the extent to which myofibrillar connectivity is evolutionarily conserved as well as mechanisms which regulate the specific architecture of sarcomere branching remain unclear. Here, we demonstrate the presence of a myofibrillar matrix in the tubular, but not indirect flight (IF) muscles within Drosophila melanogaster. Moreover, we find that loss of transcription factor H15 increases sarcomere branching frequency in the tubular jump muscles, and we show that sarcomere branching can be turned on in IF muscles by salm-mediated conversion to tubular muscles. Finally, we demonstrate that neurochondrin misexpression results in myofibrillar connectivity in IF muscles without conversion to tubular muscles. These data indicate an evolutionarily conserved myofibrillar matrix regulated by both cell-type dependent and independent mechanisms.

Subcellular Specialization of Mitochondrial Form and Function in Skeletal Muscle Cells.

Across different cell types and within single cells, mitochondria are heterogeneous in form and function. In skeletal muscle cells, morphologically and functionally distinct subpopulations of mitochondria have been identified, but the mechanisms by which the subcellular specialization of mitochondria contributes to energy homeostasis in working muscles remains unclear. Here, we discuss the current data regarding mitochondrial heterogeneity in skeletal muscle cells and highlight potential new lines of inquiry that have emerged due to advancements in cellular imaging technologies.