Biology subjects

Meinhold, M.

Publications and source records attributed to Meinhold, M..

3 recordsLinked to original sources

bioRxiv2026

Myosin binding protein-C limits strain induced cross-bridge detachment in response to rapid stretch in cardiac and skeletal muscle

Myosin binding protein-C (MyBP-C) consists of a family of regulatory proteins expressed in sarcomeres of cardiac, fast and slow twitch skeletal muscles. The 3 MyBP-C paralogs expressed in each muscle type are encoded by separate genes but maintain a similar structure. Given the overall similarity in structure and localization of each of paralog, it is assumed that MyBP-C expressed in different muscles have similar functional effects. Here we directly tested this assumption by making use of our cut and paste approach to remove and replace N-terminal regions of MyBP-C in sarcomeres of different muscle types. We found that the different MyBP-C paralogs similarly slowed cross-bridge cycling kinetics, increased Ca2+ sensitivity of tension, and damped force oscillations. However, responses to a rapid stretch in actively contracting fibers, taken as indices of cross-bridge detachment and attachment kinetics, differed in each muscle type and responses depended on the presence or absence of a given paralog of MyBP-C. Altered responses to stretch were most evident for fast MyBP-C where loss of MyBP-C in psoas muscle resulted in transient responses to stretch that resembled those found in cardiomyocytes. Replacement of cardiac MyBP-C with fast MyBP-C in cardiomyocytes led to responses similar to psoas muscle. In separate X-ray diffraction experiments we also found that loss of MyBP-C in Ca2+-activated psoas muscle increased lattice disorder, reduced the ordering of myosin heads, and decreased thin filament length. Taken together, these results indicate that the different MyBP-C paralogs exert both common and unique effects on myosin cross-bridge kinetics. Significance StatementMyBP-C is a family of regulatory proteins found in muscle sarcomeres, where they regulate contraction and relaxation. Mutations in all MyBP-C paralogs cause disease in skeletal and cardiac muscles. We used a powerful "cut and paste" strategy to selectively remove MyBP-C from slow-twitch, fast-twitch, and cardiac muscle to show that each MyBP-C effects cross-bridge behavior similarly, though to varying degrees. Each MyBP-C had a notable effect on transient responses to rapid stretch, where MyBP-C was found to limit strain-induced cross-bridge detachment, especially in fast-twitch muscles. Strain-induced cross-bridge detachment is critical for rapid filling of the left ventricle in diastole and for sustained contraction in skeletal muscle. MyBP-C paralogs appear adapted to meet the mechanical demands of each muscle type.

physiology↗

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↗