Biology subjects

Paez, H. G.

Publications and source records attributed to Paez, H. G..

3 recordsLinked to original sources

bioRxiv2026

Macroscopic to Ultrastructural Analyses Identify the Loss of Myofibrils as the Primary Mediator of Muscle Fiber Atrophy in Aging and Disuse

BackgroundAging and disuse are two of the most clinically relevant conditions associated with the loss of skeletal muscle mass, yet the ultrastructural adaptations that drive these losses remain poorly defined. In particular, it is unclear whether radial atrophy of muscle fibers is driven by a reduction in the size of the existing myofibrils, and/or the loss of myofibrils. Accordingly, the objective of this study was to define the macro-to-ultrastructural adaptations that mediate aging- and disuse-induced loss of muscle mass. MethodsSkeletal muscle structure was assessed at the macroscopic, microscopic, and ultrastructural levels in humans and mice. In humans, magnetic resonance imaging was used to quantify knee extensor muscle volume and cross-sectional area (CSA) in young (19 - 40 years) and old (65 - 84 years) adults, and vastus lateralis biopsies were analyzed for microscopic and ultrastructural adaptations using immunohistochemistry and fluorescence imaging of myofibrils with image deconvolution (FIM-ID). Parallel studies were performed in young (4 months) and aged (24 months) mice, along with the use of unilateral hindlimb immobilization to model disuse. ResultsAging led to a robust loss of skeletal muscle mass that was mediated by coordinated macro-to-ultrastructural adaptations. In humans, aging reduced knee extensor muscle volume (34%, P < 0.005) and CSA (32%, P < 0.001) in a sex-independent manner, and these effects were associated with radial atrophy of SERCA1-positive fibers (23%, P < 0.05). Ultrastructural analyses revealed that the radial atrophy was driven by a reduction in the number of myofibrils per fiber (23%, P < 0.05) without changes in myofibril CSA. In mice, aging produced similar macro-to-ultrastructural adaptations in various flexor muscles; however, radial atrophy of the highly glycolytic/Type IIb fibers, which are not present in human limb muscles, was also associated with a decrease in the CSA of the myofibrils (9%, P < 0.005). We also determined that disuse led to radial atrophy of SERCA1-positive fibers (24%, P < 0.001), and this was mediated by a decrease in both the number (22%, P < 0.005) and size of the myofibrils (4%, P < 0.05). Notably, the results also revealed that the magnitude of the disuse-induced adaptations was significantly blunted with aging. ConclusionThis study identifies the loss of myofibrils as a central and conserved mediator of the radial atrophy of muscle fibers that occurs in response to disuse and aging, while also highlighting smaller context-dependent contributions that can arise from changes in myofibril size.

physiology↗

bioRxiv2025

Mechanical Loading Induces the Longitudinal Growth of Muscle Fibers via an mTORC1-Independent Mechanism

Mechanical loading drives skeletal muscle growth, yet the mechanisms that regulate this process remain undefined. Here, we show that an increase in mechanical loading induces muscle fiber growth through two distinct mechanisms. Radial growth, reflected by an increase in fiber cross-sectional area, is mediated through an mTORC1-dependent signaling pathway, whereas longitudinal growth, marked by the in-series addition of sarcomeres, is mediated through an mTORC1-independent signaling pathway. To gain further insight into the events that drive longitudinal growth, we combined BONCAT-based labeling of newly synthesized proteins with high-resolution imaging and determined that the in-series addition of sarcomeres is mediated by a process that involves transverse splitting at the Z-lines of pre-existing sarcomeres. Collectively, our findings not only challenge the long-standing view that mechanically induced growth is uniformly governed by mTORC1, but they also lay the framework for a new understanding of the molecular and structural events that drive this process. TeaserUnlocking the Mechanical Load-Induced Growth of Skeletal Muscle: mTORC1 Doesnt Always Hold the Key.

physiology↗

bioRxiv2018

Tissue-specific dysregulation of mitochondrial respiratory capacity and coupling control in colon-26 tumor-induced cachexia

In addition to skeletal muscle dysfunction, recent frameworks describe cancer cachexia as a systemic disease involving remodeling of non-muscle organs such as adipose and liver. Impairment of mitochondrial function is associated with multiple diseases. The tissue-specific control of mitochondrial function in cancer cachexia is not well-defined. This study determined mitochondrial respiratory capacity and coupling control of skeletal muscle, white adipose tissue (WAT), and liver in colon-26 (C26) tumor-induced cachexia. Tissues were collected from PBS-injected weight-stable mice, C26 mice that were weight-stable, and C26 mice with moderate (10% weight loss) and severe cachexia (20% weight loss). WAT showed high non-phosphorylating LEAK respiration and reduced respiratory control ratio (RCR, index of OXPHOS coupling efficiency) during the induction of cachexia. Liver RCR decreased early due to cancer, and further declined with severe cachexia, where Ant2 but not Ucp2 expression was increased. Ant2 also related inversely with RCR in the liver (r=-0.547, p<0.01), suggesting a role for Ant2 in uncoupling of liver OXPHOS. Increased liver cardiolipin occurred during moderate cachexia and remained elevated in severe cachexia, suggesting this early event may also contribute to uncoupling. Impaired skeletal muscle mitochondrial respiration occurred predominantly in severe cachexia. These findings suggest that mitochondrial function is subject to tissue-specific control during cancer cachexia, whereby remodeling in WAT and liver arise early and could contribute to altered energy balance, followed by impaired skeletal muscle respiration. We highlight an underrecognized role of liver mitochondria in cancer cachexia, and suggest mitochondrial function of multiple tissues to be targets for therapeutic intervention.

physiology↗