Open research questions in Muscle Physiology and Disorders

What the literature leaves open

• Another limitation of this study is the lack of assessment of diaphragmatic motion, which has been shown to correlate with pulmonary function in DMD. A further limitation of this study is the absence of data on nocturnal hypoventilation and significant desaturation events.

  Association between thoracic ultrasound findings and respiratory function in children with Duchenne muscular dystrophy · 2026 · DOI

• Limitations of this study include the short (12-week) duration of VBP15-006, the limited amount of data from the EAP Canada period, and the relatively small sample size.

  Results of a phase II open-label, multiple-dose study of vamorolone (VBP15-006) in 7- to < 18-year-old boys with duchenne muscular dystrophy · 2026 · DOI

• In DMD, CNS involvement may also interact with physical severity, warranting further exploration of links between motor function, cognitive impairment, and emotional well-being.

  Understanding the neurobehavioural impact of Duchenne muscular dystrophy: A multicentre European study · 2026 · DOI

• Second, our investigation focused exclusively on the slow-twitch soleus muscle; whether RPW exerts similar effects on fast-twitch muscles, such as the plantaris or gastrocnemius, remains an open question for future investigation. Several limitations of the present study should be acknowledged.

  Radial pressure wave treatment accelerates recovery from immobilization-induced soleus muscle atrophy and improves ankle range of motion in mice · 2026 · DOI

• Another potential limitation of this study is that the height of the non-ambulant cohort was estimated using predictive equations derived from healthy individuals. These findings should be further investigated in larger longitudinal studies taking into account several aspects of standards of care prospectively collected.

  Vertebral fractures and muscle function in glucocorticoid-treated individuals with Duchenne muscular dystrophy: a cohort study · 2026 · DOI

• The larger SC type 1 fibres in T2DM may reflect chronic loading associated with higher body mass and sustained postural activity, although causal inference is limited by the cross-sectional, post-mortem design.

  Fibre morphology, intramyocellular lipid content and 3D capillary architecture in human postural, respiratory and locomotor muscles in type 2 diabetes mellitus · 2026 · DOI

• A major limitation in the field has been the lack of validated mammalian models that faithfully recapitulate the defining histopathological features of XMEA. X-Linked myopathy with excessive autophagy (XMEA) is a rare genetic muscle disease caused by mutations in Vma21, yet the mechanisms linking Vma21 deficiency to progressive muscle pathology in vivo remain poorly understood.

  VMA21 deficiency leads to autophagic dysregulation and altered vesicle trafficking in X-linked myopathy with excessive autophagy · 2026 · DOI

• Our findings also need to be interpreted in the context of the wider bibliometric landscape of muscle and ageing research.

  Global MyoG research 2004–2024: a bibliometric analysis of trends and translational implications · 2026 · DOI

• Whether alternative splicing continues to advance as muscle unloading persists beyond 14 days remains to be established, but splicing is a regulatory step in gene expression to determine which part of the genetic sequence is finally used in synthesizing new proteins and can dictate protein variability in skeletal muscle.

  Differential alternative splicing in skeletal muscle after 14 days immobilization-induced atrophy in young men · 2026 · DOI

• The pathophysiological mechanism underlying HF-induced skeletal muscle atrophy is highly intricate and not fully understood. Abnormal mitochondrial metabolism is regarded as one of the earliest indicators that trigger skeletal muscle atrophy, but the underlying mechanisms are unclear. The role of GNMT in HF-induced skeletal muscle atrophy has not been previously explored.

  GNMT alleviates heart failure-induced skeletal muscle atrophy by regulating ATP5J2-mediated mitochondrial metabolic reprogramming through succinylation · 2026 · DOI

• One challenge is the lack of effective treatments for congenital muscular dystrophy type 1A (CMD1A). Another challenge is understanding the mechanisms underlying the effects of anti-RANKL treatment on muscle and bone. A technical challenge is the development of effective methods for evaluating muscle and bone function in mouse models of CMD1A.

  Anti–Receptor Activator of Nuclear Factor-κB Ligand Improves Muscle Dysfunction and Strengthens Bone in Laminin-α2–Deficient dy2J/dy2J Dystrophic Mice · 2026 · DOI

• How this limited DUX4 expression leads to definitive target gene activation and how these downstream genes contribute to FSHD pathology remain elusive.

  LEUTX mediates amplification of DUX4 signaling and aberrant myotube differentiation in facioscapulohumeral muscular dystrophy · 2026 · DOI

• Little is known about the mechanism for maintaining quality of the proteins in young and growing muscles despite that they likely face constant challenges to the protein quality control (PQC).

  TGF-β/activin signaling balances the activity of two major protein quality control mechanisms during growth of Drosophila larval body wall muscle · 2026 · DOI

• It notes the need to integrate RNA-seq and LC-MS/MS data to assess the agreement between the transcriptome and proteome. It highlights the importance of constructing a PPI network to predict the functions and interrelationships of DEGs.

  Multi-Omics and RNAi Reveal a Role for the Ubiquitin-Proteasome Pathway in Muscle Fiber Development of Common Carp (Cyprinus carpio) · 2026 · DOI

• It notes the need to investigate the correlation between mRNA expression and protein abundance. It highlights the importance of understanding the ubiquitin-proteasome pathway's role in muscle fiber development.

  Multi-Omics and RNAi Reveal a Role for the Ubiquitin-Proteasome Pathway in Muscle Fiber Development of Common Carp (Cyprinus carpio) · 2026 · DOI

• Second, while A4 < 3kDa showed protective effects against dexamethasone-induced atrophy, its direct role in anabolic signaling and lack of hypertrophic effect under normal conditions remain unclear. Lastly, further research using alternative animal-derived protein sources is warranted to more comprehensively evaluate the anti-atrophic potential of A4 < 3kDa.

  Horse Meat Hydrolysate Ameliorates Dexamethasone-Induced Muscle Atrophy in C57BL/6 Mice via the AKT/FoxO3a/mTOR Pathway · 2025 · DOI

• Future research should focus on integrating B3 and B6 into multimodal strategies, including resistance training, adequate protein intake, and vitamin D supplementation, and developing biomarker-guided, personalized interventions.

  Nicotinamide and Pyridoxine in Muscle Aging: Nutritional Regulation of Redox, Inflammation, and Regeneration · 2025 · DOI

• Despite growing interest in nicotinamide and pyridoxine as modulators of muscle aging, several critical gaps remain in our understanding of their mechanisms, optimal applications, and long-term outcomes. Addressing these gaps will require coordinated advances in basic science, clinical research, and precision nutrition.

  Nicotinamide and Pyridoxine in Muscle Aging: Nutritional Regulation of Redox, Inflammation, and Regeneration · 2025 · DOI

• A comprehensive characterization of the cell populations of FAPs and fibroblasts is still lacking. Given the complexity of these cell populations, it is unfeasible to label or isolate the different FAP or fibroblast cell populations to observe their communication with MuSCs.

  Muscle Stem Cell Microenvironment and Functions in Muscle Regeneration · 2025 · DOI

• Polymorphisms in TRHR have been associated with sarcopenia, an age-related disorder characterized by muscle atrophy and functional decline, although its specific regulatory mechanism remains unclear.

  Transcriptomic Insights Reveal PRTFDC1 as a Novel Regulator of Myogenic Differentiation in Sujiang Pig Satellite Cells · 2025 · DOI

• The mechanisms for persistent sinus tachycardia in early DMD cardiomyopathy remain undetermined but may be due to autonomic dysfunction, decline in myocardial compliance, or regional myocardial abnormalities.

  Sinus Tachycardia and Unrelieved Wall Stress Precede Left Ventricular Systolic Dysfunction During Preclinical Cardiomyopathic Changes in Duchenne Muscular Dystrophy · 2025 · DOI

• However, in vivo evidence in a mammalian model organism for the role of POGLUT1 in the developing myogenic progenitors and in adult satellite cells was lacking.

  The glycosyltransferase POGLUT1 regulates muscle stem cell development and maintenance in mice · 2025 · DOI

• Taken together, the evidence reviewed here supports a conceptual shift from cataloguing molecules detected in muscle or blood toward defining the conditions under which a candidate myokine has physiological or pathological relevance. A stepwise framework integrating the principal requirements for this interpretation and for subsequent clinical translation is summarized in Figure 3.

  The Myokine Landscape: Sources, Signaling, and Context-Dependent Actions · 2026 · DOI

• However, interpretation of these results is limited by the fact that, among the 27 unresolved cases, 9…

  Pediatric HyperCKemia: a 13-year retrospective study and predictors of neuromuscular disease and metabolic myopathy · 2026 · DOI

• Investigating the long-term effects of anti-RANKL treatment, - Examining the effects of anti-RANKL treatment on other muscular dystrophy models, - Studying the mechanisms underlying the anti-inflammatory effects of anti-RANKL…

  Anti–Receptor Activator of Nuclear Factor-κB Ligand Improves Muscle Dysfunction and Strengthens Bone in Laminin-α2–Deficient dy2J/dy2J Dystrophic Mice · 2026 · DOI

Most-cited papers in Muscle Physiology and Disorders

• Regulation of skeletal muscle mass in mice by a new TGF-p superfamily member · Nature · 1997 · 3,455 citations
• Direct Gene Transfer into Mouse Muscle in Vivo · Science · 1990 · 3,320 citations
• Identification of Ubiquitin Ligases Required for Skeletal Muscle Atrophy · Science · 2001 · 3,038 citations
• Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension · Nature · 1997 · 2,501 citations
• Transcriptional co-activator PGC-1α drives the formation of slow-twitch muscle fibres · Nature · 2002 · 2,230 citations
• Muscle Regeneration by Bone Marrow-Derived Myogenic Progenitors · Science · 1998 · 2,148 citations
• The muscular dystrophies · The Lancet · 2002 · 1,296 citations
• Mechanisms of muscle atrophy and hypertrophy: implications in health and disease · Nature Communications · 2021 · 912 citations
• Single-Cell Analysis of the Muscle Stem Cell Hierarchy Identifies Heterotypic Communication Signals Involved in Skeletal Muscle Regeneration · Cell Reports · 2020 · 411 citations
• Skeletal muscle atrophy: From mechanisms to treatments · Pharmacological Research · 2021 · 397 citations

Most recent work

• Leukaemia inhibitory factor - an exercise-induced myokine · PubMed · 2026
• Exercise, skeletal muscle and inflammation: ARE-binding proteins as key regulators in inflammatory and adaptive networks · PubMed · 2026
• Molecular mechanisms of skeletal muscle atrophy: clinical challenges and future therapeutic strategies · Biochemical Pharmacology · 2026
• The central role of macrophages in skeletal muscle regeneration: Phenotypic Polarization, metabolic reprogramming, and therapeutic prospects · Biochemical Pharmacology · 2026
• Skeletal muscle metabolism in health and disease: Mechanisms, interventions, and clinical perspectives · iScience · 2026
• Decoding the Endocrine Code of Skeletal Muscle: Myokines, Exerkines, and Inter-Organ Crosstalk in Metabolic Health and Disease · Cells · 2026
• Now with oligos: antibody–oligonucleotide conjugates are the new drug modality to watch · Nature Biotechnology · 2026
• Apitegromab for lean mass preservation during tirzepatide-induced weight loss: a randomized, double-blind, placebo-controlled phase 2 trial · Nature Medicine · 2026
• Mechanisms of protein degradation in atrophying muscles: What have we learned during the past decade? · Journal of Biological Chemistry · 2026
• Immunometabolic reprogramming of macrophages: Emerging roles in skeletal muscle regeneration and therapeutic perspectives · Pharmacological Research · 2026

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