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Open research questions in Muscle Physiology and Disorders

36 unresolved questions extracted from the limitations and future-work sections of 329 Muscle Physiology and Disorders papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • 5,34-37 While the exact mechanism remains unclear, local signalling post-injury and baseline diferences in FAP subpopulations are thought to play a major role in infuencing FAPs toward fbroblast diferentiation.

    Phenotypic divergence in rotator cuff tear and volumetric muscle loss mouse models following fibroadipogenic progenitor depletion · 2026 · DOI

  • Although microtubules (MT) are established regulators of striated muscle mechanics, how MT lattice organization and post-translational modifications (PTM) individually shape contractility in healthy skeletal muscle fibers remains incompletely understood.

    Microtubule architecture and detyrosination bidirectionally modulate sarcomere shortening in skeletal muscle fibers · 2026 · DOI

  • Previous whole-transcriptome analysis has shown that Insulin-like Growth Factor 1 (IGF1) is significantly upregulated in Yili horses following racing and is involved in the PI3K-Akt signaling pathway; however, its specific regulatory mechanism in equine skeletal muscle cells remains unclear.

    Effects of IGF1 Knockdown and Overexpression on the Phenotype and Function of Equine Primary Skeletal Muscle Cells · 2026 · DOI

  • nutrition 89). Whole-course management, encompassing preoperative, perioperative, and postoperative phases, has demonstrated efficacy in preserving skeletal muscle mass in gastric cancer patients undergoing continuous, neoadjuvant multidisciplinary nutritional oversight may be superior to episodic supplementation (90). In breast cancer, multimodal interventions combining supervised exercise with tailored nutritional support have already shown preliminary efficacy in postoperative reducing for the complication integrated, rather than siloed, supportive care.

    Sarcopenia in breast cancer: prognostic values and emerging therapeutic strategies · 2026 · DOI

  • ABSTRACT Background Dnajb5, a member of the heat shock protein family, has not been previously reported to play a role in muscle differentiation.

    Dnajb5 From Antarctic Fish Reveals a Redox‐Sensitive Mechanism Coordinating Muscle Regeneration via mTORC1 and HDAC4 · 2026 · DOI

  • Laiwu pigs represent a valuable model for studying IMF deposition due to their extremely high IMF content, yet the regulatory mechanisms of chromatin accessibility in skeletal muscle remain unclear.

    Integrative ATAC-Seq and RNA-Seq analysis identifies key genes for intramuscular fat content in Laiwu pigs · 2026 · DOI

  • Imaging-based alternatives have been suggested, particu- larly for assessing CNS involvement and muscle health, but their development is impeded by high costs limiting acces- sibility and a lack of standardized protocols.

    Current biomarker development in myotonic dystrophies · 2026 · DOI

  • Despite FDA approval of weight-loss medications for adolescents, including phentermine/topiramate (PHEN/TPM), there is limited evidence for their use in children with DMD, particularly regarding potential cardiac complications in a population already at elevated risk.

    Outcomes of phentermine-topiramate in children living with Duchenne muscular dystrophy · 2026 · DOI

  • Background Duchenne muscular dystrophy (DMD) is associated with cognitive deficits and neural abnormalities, yet how temporal properties of regional brain activity align with structural changes across development remains unclear.

    Cognitive deficits linked to intrinsic timescales and gray matter volume abnormalities in children with Duchenne muscular dystrophy · 2026 · DOI

  • Interestingly, both VWR and GSK3 inhibition with lithium can exert neuroprotective effects against Alzheimer's pathology; however, whether this treatment can also benefit cognitive function in mdx mice remains unknown.

    Voluntary wheel running combined with low-dose lithium supplementation improves novel object recognition in male DBA/2 J mdx mice · 2026 · DOI

  • BACKGROUND: Dp140-related mutations associate with neurodevelopmental impairments in Duchenne muscular dystrophy (DMD), their effects on cortical similarity network organization remain unclear.

    Relationship Between Dp140 Genotype and Cortical Similarity Network Phenotype in Duchenne Muscular Dystrophy: Preliminary <scp>T1</scp> Weighted Study · 2026 · DOI

  • Current research highlights a strong interplay between microenvironmental signaling and the regulation of gene expression during muscle regeneration. While significant progress has been made in defining individual signaling pathways and their downstream targets, the mechanisms by which diverse niche-derived signals are integrated to produce coordinated transcriptional responses remain incompletely understood. In particular, although there is clear evidence that signaling pathways converge on key transcription factors such as MyoD, how these inputs are combined within the broader context of enhancer regulation and chromatin architecture remains to be fully defined. A major challenge moving forward will be to determine how multiple signaling inputs are simultaneously interpreted at specific enhancer elements in vivo. Most current studies examine signaling pathways in isolation or infer convergence through computational analyses, rather than directly testing how combinations of signals influence enhancer activity, chromatin accessibility, and enhancer-promoter interactions. Addressing this question will be critical to understanding how MuSCs generate precise, context-dependent gene expression programs in response to complex niche environments. Advances in multi-omics technologies provide new opportunities to address these questions. Single-cell approaches, including scRNA-seq in combination with computational frameworks such as CellChat and NicheNet, can be used to infer intercellular communication within the niche [137,138]. In parallel, multimodal techniques such as TEA-seq and multi- CUT&Tag enable the simultaneous profiling of chromatin accessibility, transcriptional output, and protein-chromatin interactions within the same cells [139,140]. Integration of these approaches with methods that capture three-dimensional genome organization will be particularly important for linking signaling inputs to changes in enhancer landscapes and chromatin architecture. Together, future studies that combine these approaches will be essential for bridging the current gap between niche-derived signaling and enhancer-mediated gene regulation, and for defining how these processes are coordinated to drive effective muscle regeneration.

    Enhancers integrate microenvironmental signals in muscle stem cells during regeneration in health, disease, and aging · 2026 · DOI

  • This study has several limitations. First, the quality of the original literature is limited. The lack of blinding and allocation concealment in some experiments may introduce a certain degree of selection and performance bias. Furthermore, the overall certainty of evidence, as assessed by the GRADE framework, was rated as very low due to concerns regarding risk of bias, indirectness, and imprecision. This necessitates cautious interpreta- tion of the pooled effect estimate and underscores the need for higher-quality evidence to inform clinical prac- tice.Second, although comprehensive search strategies were used, the rank correlation test within the multi- level framework indicated potential small-study effects or publication bias. While sensitivity analyses suggested the main finding was stable, this potential bias may affect the precision of the effect size estimate, necessi- tating cautious interpretation and verification by future large-scale studies.Additionally, the exercise intervention parameters (such as intensity, duration, and frequency) varied across studies, preventing a quantitative analy- sis of the optimal RT parameters. Meanwhile, there was significant heterogeneity in the control interventions. The control conditions ranged from passive usual care to active health education or nutritional supplementation. This variability introduces uncertainty: active control measures may themselves affect outcomes, potentially attenuating between-group differences attributable to RT; conversely, passive controls may overestimate effect sizes.Third, there is a lack of direct mechanistic evidence. Current research on the mechanisms by which exercise modulates serum MSTN levels is largely based on animal or in vitro studies, with a scarcity of physiological and molecular mechanistic studies specifically targeting older adults with sarcopenia/frailty. Furthermore, most studies exploring the relationship between MSTN and sarcope- nia/frailty rely on logical inferences or indirect evidence, lacking direct experimental validation. This may limit the ability to firmly establish causality or elucidate specific regulatory pathways, thereby constraining the in-depth interpretation of the intervention effects. Finally, there is insufficient assessment of long-term effects. Most of the included studies involved short-term interventions, with a lack of follow-up evidence lasting one year or longer. This hinders the evaluation of the sustainability and long- term impact of RT on serum MSTN levels in older adults with sarcopenia or frailty.

    The effects of resistance training on myostatin in older adults with frailty and/or sarcopenia: a systematic review and meta analysis · 2026 · DOI

  • Transcriptomic advances in studies of muscle stem cell aging: From bulk to single-cell and beyond, Seung Pil Pack1 and Thomas A. Rando2,3 ✉ Soochi Kim 1 ✉ © The Author(s) 2026 Advances in transcriptomic technologies have progressively transformed the questions we can ask and answer about muscle stem cells (MuSCs) during aging. Early microarray and bulk RNA sequencing studies established foundational population-level signatures of aged MuSCs, including attenuation of myogenic and metabolic programs as well as induction of inflammatory and stressassociated transcription. However, these averaged readouts obscured cell-to-cell variability and rare functional states. The transition to single-cell and single-nucleus RNA sequencing marked a turning point by resolving MuSC heterogeneity and revealing that MuSC aging is not purely stochastic. Instead, aged MuSC pools show reproducible changes in state composition, delayed or altered myogenic lineage progression, and selective vulnerability of specific functional subsets. Emerging spatial transcriptomic approaches, although still limited by sensitivity and cell-type discrimination in muscle, are beginning to place these MuSC states into their native tissue context, directly linking transcriptional states, niche organization, and age-associated remodeling. In parallel, integrative multi-omic designs that pair transcriptomics with chromatin accessibility and metabolic measurements have strengthened mechanistic connections among age-associated gene programs, epigenetic remodeling, and metabolic state shifts. Finally, computational frameworks — including trajectory inference, dynamic modeling, and machine learning — are increasingly applied to high-dimensional transcriptomic data to predict aging trajectories and identify candidate rejuvenation targets. In this Perspective, we trace the evolution of transcriptomic technologies through the lens of MuSC aging and highlight how increasing resolution has reframed core models of MuSC decline and plasticity.:,;) ( 0 9 8 7 6 5 4 3 2 1 Cell Research (2026) 0:1–9; https://doi.org/10.1038/s41422-026-01240-w INTRODUCTION Skeletal muscle regeneration depends on the activity of muscle stem cells (MuSCs), also known as satellite cells, which reside in a lamina of muscle fibers.1–3 quiescent state beneath the basal Upon injury or stress, MuSCs activate, proliferate, and differentiate to repair damaged tissue while maintaining the stem cell pool through self-renewal.4,5 With aging, however, this tightly regulated balance becomes disrupted. Aged MuSCs exhibit reduced regenerative capacity, increased susceptibility to senescence, and altered responses to environmental cues.6–8 Understanding the molecular mechanisms that underlie MuSC aging has long been a central challenge in regenerative biology.

    Transcriptomic advances in studies of muscle stem cell aging: From bulk to single-cell and beyond · 2026 · DOI

  • &#x0D; Results : In this study, there were 2 out of 5 (40%) positive alpha-SMA expressions with history of recurrent contraction, 2 (40%) negative expressions with no history of recurrent contraction, and 1 result that could not be assessed due to the limited number of samples containing fibroblasts in patient with history of recurrent contraction.

    THE EXPRESSION OF ALPHA-SMOOTH MUSCLE ACTIN IN CONTRACTED SOCKET · 2024 · DOI

  • G protein-coupled receptor 81 (GPR81), a selective receptor for lactate, expresses in skeletal muscle cells, but the physiological role of GPR81 in skeletal muscle has not been fully elucidated.

    Activation of Lactate Receptor Positively Regulates Skeletal Muscle Mass in Mice · 2023 · DOI

  • The regulation of cytokine production in skeletal muscle cells has been relatively well studied, yet little is known about the compensatory and anti-inflammatory mechanisms that resolve inflammation and restore tissue homeostasis.

    Exercise, skeletal muscle and inflammation: ARE-binding proteins as key regulators in inflammatory and adaptive networks · 2026 · DOI

  • However, primary human SCs and FAPs are difficult to co-isolate, and their broad use in translational research has been limited by a lack of standardized biobanking protocols.

    A Multi-Institution Biobanking Pipeline for Primary Human Satellite Cells and Fibro-Adipogenic Progenitors · 2026 · DOI

  • Despite these clear associations, clinical translation is currently hindered by heterogeneous diagnostic criteria and the lack of standardized this, incorporating composition assessments into routine oncological care is essential for early risk stratification.

    Sarcopenia in breast cancer: prognostic values and emerging therapeutic strategies · 2026 · DOI

  • New & NoteworthyPhysiological roles of the mammalian homologs of bacterial LanC, LanCLs, are poorly understood.

    Loss of LanC-like proteins impairs post-injury regeneration of aging muscles · 2026 · DOI

  • In this review, we provided a summary of the impact of physical activity both in animal models and in patients with Becker's muscular dystrophy, with the intent to identify trends and gaps in knowledge.

    Motor activity and Becker’s muscular dystrophy: lights and shadows · 2019 · DOI

  • Numerous studies have been conducted on electrical, extending and magnetic stimulation of cells, but the effect of centrifugal force on cells remains to be investigated.

    Expression of Myosin Heavy-chain mRNA in Cultured Myoblasts Induced by Centrifugal Force · 2008 · DOI

  • However, a clinically reliable differentiation stimulus for three-dimensional (3-D) cultures is necessary for this process, and this condition has not yet been established.

    Shell and Tube Heat Exchanger Design Software for Educational Applications · 1998 · DOI

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36 open questions have been extracted from the limitations and future-work passages of 329 Muscle Physiology and Disorders papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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