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1. Myosin cross-bridge kinetics slow at longer muscle lengths during isometric contractions in intact soleus from mice

   https://doi.org/10.1098/rspb.2020.2895  

   Fenwick, Axel J.; Lin, David C.; Tanner, Bertrand C. (May 2021, Proceedings of the Royal Society B: Biological Sciences)

   null (Ed.)

   Muscle contraction results from force-generating cross-bridge interactions between myosin and actin. Cross-bridge cycling kinetics underlie fundamental contractile properties, such as active force production and energy utilization. Factors that influence cross-bridge kinetics at the molecular level propagate through the sarcomeres, cells and tissue to modulate whole-muscle function. Conversely, movement and changes in the muscle length can influence cross-bridge kinetics on the molecular level. Reduced, single-molecule and single-fibre experiments have shown that increasing the strain on cross-bridges may slow their cycling rate and prolong their attachment duration. However, whether these strain-dependent cycling mechanisms persist in the intact muscle tissue, which encompasses more complex organization and passive elements, remains unclear. To investigate this multi-scale relationship, we adapted traditional step-stretch protocols for use with mouse soleus muscle during isometric tetanic contractions, enabling novel estimates of length-dependent cross-bridge kinetics in the intact skeletal muscle. Compared to rates at the optimal muscle length ( L o ), we found that cross-bridge detachment rates increased by approximately 20% at 90% of L o (shorter) and decreased by approximately 20% at 110% of L o (longer). These data indicate that cross-bridge kinetics vary with whole-muscle length during intact, isometric contraction, which could intrinsically modulate force generation and energetics, and suggests a multi-scale feedback pathway between whole-muscle function and cross-bridge activity. 

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2. Feats of supercontractile strength: functional convergence of supercontracting muscle properties among hyoid musculature in chameleons

   https://doi.org/10.1098/rspb.2025.0078  

   Schneider, Nikole G; Henchal, Nicholas A; Diaz_Jr, Raul E; Anderson, Christopher V (March 2025, Proceedings of the Royal Society B: Biological Sciences)

   The structure of sarcomeres imposes limits to the capacity of striated muscle to change length and produce force, with z-disc and myosin filament interactions constraining shortening. Conversely, supercontracting muscles, hitherto only known among vertebrates in the tongue retractor muscle (m. hyoglossus) of chameleons, have perforated z-discs that allow myosin filaments to extend through them into adjacent sarcomeres, permitting continued shortening and force development. Additional hyolingual muscles in chameleons undergo extreme length changes during feeding as well and may benefit from supercontractile properties. We compared length–tension relationship data and transmission electron microscopy images from four chameleon muscles to test for the presence of additional supercontracting muscle. We document the second known example of a supercontracting muscle among vertebrates (the m. sternohyoideus superficialis) and show that the m. sternohyoideus profundus exhibits functional convergence with supercontracting muscles by increasing the range of muscle lengths over which it can exert force through the exploitation of sarcomere length non-uniformity across its muscle fibres. Additionally, we show that chameleon supercontracting muscles may share common contractile and structural properties due to a common origin from occipital somites. These results provide important insights into the developmental and evolutionary patterns associated with supercontracting muscle and extreme muscle elongation. 

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3. BPS2025 - Cross-scale conundrum: Slow masticatory myosin in jaw muscles that are both fast and strong

   https://doi.org/10.1016/j.bpj.2024.11.758  

   Dhorajia, Varun V; LaFave, Nicholas; Reder, Brandon; Brocklehurst, Robert; Konow, Nicolai; Walcott, Sam; Moore, Jeffrey R (February 2025, Biophysical Journal)

   Masticatory myosin (MHC-M) is expressed in jaw muscles of some vertebrates where it has been associated with bites that are both swift and forceful, contrary to the century old paradigm of a muscle force-velocity tradeoff. However, deciphering myosin's molecular properties from constituent muscle properties is complicated as muscle contractile properties are determined by a complex interplay between molecular, cellular, and organ-scale structure and function. Therefore, we applied a multiscale approach to link MHC-M's molecular properties to its constituent jaw muscle properties. Myosin isoform analysis using SDS-PAGE revealed a strong association of MHC-M with jaw closing function. Furthermore, in-situ ergometry revealed that fascicles of jaw closing gray squirrel superficial masseter (SM-GS), which expresses MHC-M, produced ∼1.6-fold greater tension (13.52 N/g ± 4.0 N/g) compared to superficial masseter in rats (SM-Rt; 8.48 N/g ± 1.09 N/g), which only contains MHC-II. Greater SM-GS force was coupled with a ∼1.8-fold faster peak shortening velocity (SM-GS = 72.78 mm/s ± 16.02 mm/s; SM-Rt = 40.63 mm/s ± 3.19 mm/s). In contrast to predictions based on contractile parameters at higher scale of muscle organization, MHC-M from SM-GS propelled actin at ∼5-fold slower unloaded velocity (VACTIN = 0.8 μm/sec ± 0.1 μm/sec) in vitro compared to MHC-II from SM-Rt (4.3 μm/sec ± 1.4 μm/sec). The apparent disconnect between cross-scale contractile properties of these jaw muscles may be accounted for by factors like respective myosin's propensity for weak binding and/or thick filament activation. Our latest multi-scale mathematical model accounts for such factors and reasonably recapitulates whole-muscle, muscle-fiber, and in vitro velocities. Further refinements to this model will guide our investigation of additional factors, including thin filament regulation, extracellular matrix mechanics, and fiber architecture, to ultimately connect molecular action of MHC-M more directly to in-vivo force measurements of rodent bites. 

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4. Contractile work directly modulates mitochondrial protein levels in human engineered heart tissues

   https://doi.org/10.1152/ajpheart.00055.2020  

   Ng, Ronald; Sewanan, Lorenzo R.; Brill, Allison L.; Stankey, Paul; Li, Xia; Qyang, Yibing; Ehrlich, Barbara E.; Campbell, Stuart G. (June 2020, American Journal of Physiology-Heart and Circulatory Physiology)

   null (Ed.)

   Engineered heart tissues (EHTs) have emerged as a robust in vitro model to study cardiac physiology. Although biomimetic culture environments have been developed to better approximate in vivo conditions, currently available methods do not permit full recapitulation of the four phases of the cardiac cycle. We have developed a bioreactor which allows EHTs to undergo cyclic loading sequences that mimic in vivo work loops. EHTs cultured under these working conditions exhibited enhanced concentric contractions but similar isometric contractions compared with EHTs cultured isometrically. EHTs that were allowed to shorten cyclically in culture had increased capacity for contractile work when tested acutely. Increased work production was correlated with higher levels of mitochondrial proteins and mitochondrial biogenesis; this effect was eliminated when tissues were cyclically shortened in the presence of a myosin ATPase inhibitor. Leveraging our novel in vitro method to precisely apply mechanical loads in culture, we grew EHTs under two loading regimes prescribing the same work output but with different associated afterloads. These groups showed no difference in mitochondrial protein expression. In loading regimes with the same afterload but different work output, tissues subjected to higher work demand exhibited elevated levels of mitochondrial protein. Our findings suggest that regulation of mitochondrial mass in cultured human EHTs is potently modulated by the mechanical work the tissue is permitted to perform in culture, presumably communicated through ATP demand. Precise application of mechanical loads to engineered heart tissues in culture represents a novel in vitro method for studying physiological and pathological cardiac adaptation. NEW & NOTEWORTHY In this work, we present a novel bioreactor that allows for active length control of engineered heart tissues during extended tissue culture. Specific length transients were designed so that engineered heart tissues generated complete cardiac work loops. Chronic culture with various work loops suggests that mitochondrial mass and biogenesis are directly regulated by work output. 

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5. Profiling the epigenomic landscape of late embryonic and adult mouse hind limb muscles

   https://doi.org/10.1038/s41598-025-32705-4  

   Queeno, Samantha R; Okamoto, Alexander S; Callahan, Damien M; O’Neill, Matthew C; Capellini, Terence D; Sterner, Kirstin N (February 2026, Scientific Reports)

   Skeletal muscles are essential for movement, supporting a wide range of locomotor behaviors. Muscle tissue is composed of multiple cell types including “fast” and “slow” myofibers, whose contractile properties are largely influenced by selective expression of myosin heavy chain (MyHC) isoforms. While ‘super-enhancers’ regulating MyHC gene clusters have been identified, the cis-regulatory elements (CREs) controlling non-MyHC genes important to myofiber physiology remain less defined. Here, we profile the regulatory landscape of two pairs of mouse hind limb muscles differing in MyHC expression at a late embryonic (E18.5) and adult time point to identify candidate CREs that may regulate genes important to myofiber type. Gene expression and chromatin accessibility analyses revealed that epigenetic differences at E18.5 largely reflect limb patterning, whereas adult differences reflect myofiber differentiation. We identified thousands of differentially accessible regions that may regulate genes important for muscle development, muscle biology, and myofiber identity. Among these, twelve conserved, muscle-specific CREs associated with myofiber type were tested for regulatory activity. Nine enhanced and three reduced gene activity in vitro, although their phenotypic effects remain unknown. By profiling multiple muscles across two time points, our study extends current understanding of conserved, muscle-specific CREs that regulate gene expression during myogenesis. 

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