Kristian Vissing

Stem cell transition from quiescence to activation is crucial to guarantee productive tissue regeneration. Here, we show that CD90 expression diversifies quiescent muscle stem cells (MuSCs) in murine and human muscle into two subsets differing in the kinetics of activation. CD90+ve MuSCs exhibit a faster exit from quiescence and predominate the initial phases of regeneration compared to CD90-ve MuSCs. In the absence of injury, the CD90+ve fraction is primed towards activation through an active CD90-AMPK axis but is maintained in quiescence through signals from the extracellular matrix. We further show that Collagen VI, which is preferentially expressed by CD90+ve MuSCs, binds to the Calcitonin receptor. Moreover, while the number of CD90+ve and CD90-ve MuSCs is similar in healthy muscles, the CD90-ve fraction predominates in muscles of murine models of Duchenne and Ullrich congenital muscular dystrophies. These findings provide novel insights into the mechanistic determinants of MuSCs functional heterogeneity and have implications for understanding the stimulation of repair in dystrophic muscle.

Purpose: Diabetic polyneuropathy (DPN) is a debilitating complication of diabetes that affects motor nerves and may impair skeletal muscle health. This study investigated skeletal muscle proteomic alterations associated with DPN compared with type 2 diabetes without DPN (T2D) and healthy controls (CON). Experimental Design: An exploratory proteomic profiling was performed in 15 participants divided into three groups based on clinical and neurophysiological diagnosis (DPN, n = 5; T2D, n = 5; CON, n = 5). Biopsies from the gastrocnemius lateralis muscle were analyzed using LC‐MS/MS–based proteomics and pathway enrichment analyses. Results: A total of 265 and 444 proteins were differentially expressed in DPN compared with T2D and CON, respectively (q < 0.05). Enrichment analyses revealed marked alterations in mitochondrial‐related pathways, including cellular respiration, distinguishing DPN from both comparison groups. Differences between T2D and CON were present but less pronounced. DPN was characterized by downregulation of glycogen‐regulating proteins (phosphorylase kinase G1 and A1) and upregulation of ferritin light chain (FTL), alpha actin 2, and myosin‐binding protein H. Conclusions and clinical relevance: DPN is associated with a distinct and progressive skeletal muscle proteomic phenotype, supporting mitochondrial dysfunction as a key feature and providing a basis for future mechanistic and therapeutic studies.

Fibro-adipogenic progenitors (FAPs) have emerged as central regulators of the skeletal muscle homeostasis and the muscle microenvironment. However, the role of FAPs in the context of exercise-induced muscle hypertrophy remains largely unexplored. Here, we utilized six weeks of blood flow restricted resistance exercise (BFRRE) to study cellular adaptations within the muscle microenvironment accompanying muscle hypertrophy in healthy older individuals. Using flow cytometry, we characterized global changes of key cell populations within the skeletal muscle microenvironment, including FAPs, muscle stem cells (MuSCs), and immune cells. BFRRE induced significant enlargement of both FAPs and MuSCs, consistent with cellular adaptation to exercise. Notably, exercise shifted the FAP pool toward an increased predominance of the CD90 ^high FAP phenotype, without altering total FAP abundance. In addition to matrix and collagen-related genes, transcriptional analysis of genes associated with secretory proteins revealed enrichment of pro-myogenic factors in CD90 ^high versus CD90 ^low FAPs. Conditioned media experiments of freshly isolated FAPs demonstrated that CD90 ^high FAPs promote myotube growth in vitro compared to CD90 ^low counterparts, suggesting that this phenotypic shift may facilitate muscle hypertrophy. In parallel, BFRRE increased the proportion of pro-inflammatory (CD11c+) macrophages within the skeletal muscle niche, highlighting a dynamic immune response during adaptation. Finally, we show identified possible link between pro-inflammatory macrophages and FAPs, as TNFα markedly reduced the proliferation of human primary FAPs ex vivo , suggesting that macrophage-derived signals may attenuate excessive FAP expansion during tissue remodelling. Together, these findings provide new insight into how the remodelling of the cellular niche may support muscle hypertrophy in response to exercise. The coordinated expansion and phenotypic remodeling of FAP and immune cell populations may represent an important mechanism through which exercise supports hypertrophy in older individuals. Key Points: The role of FAPs in human exercise-induced hypertrophy remains poorly understood. Exercise-induced hypertrophy increased FAP size and the proportion of CD90 ^high FAPs. CD90 ^high FAPs expressed growth-promoting ligands and enhanced myotube growth through secreted factors compared to CD90 ^low FAPs. CD11c⁺ macrophage expansion correlated with CD90 ^high FAP and MuSC responses, while TNF-α inhibited FAP proliferation ex vivo. The results highlight remodelling of FAP subpopulations as a potential contributor to exercise-induced hypertrophy of aging skeletal muscle.

Ischemic heart disease remains a major global health burden, with ischemia-reperfusion injury representing a critical determinant of myocardial damage. Remote ischemic conditioning (RIC) and differentiated physical exercise regimens have emerged as potential preconditioning strategies enhancing myocardial resilience, and increasing evidence suggests that these cardioprotective effects may, in part, be mediated by targeted delivery of extracellular vesicle (EV)-carried microRNAs (miRNAs). RIC induces rapid alterations in circulating EV cargo, including miRNAs known to promote cell survival, attenuate oxidative stress, and modulate inflammation. This transient yet pronounced miRNA response to RIC indicates a rapid EV-associated molecular change that may be relevant to early signaling events underlying remote organ preconditioning. EV-miRNA content also changes acutely in response to exercise. These changes are associated with vascular remodeling, anti-apoptotic signaling, and metabolic adaptations, suggesting that exercise-induced EVs provide both immediate and sustained cardioprotection, although temporal dynamics remain incompletely defined. Consequently, RIC and exercise elicit distinct yet overlapping EV-miRNA signatures that may affect myocardial preconditioning. Here, we review whether EV-delivered miRNAs elicited by RIC and exercise may contribute to cardioprotection and may be therapeutically exploited in clinical settings such as heart failure and ischemic disease.

Introduction: Age-related declines in skeletal muscle mass and function are partly attributed to anabolic resistance, a diminished stimulation of muscle protein synthesis (MPS) following nutrient intake or exercise. However, the magnitude and physiological specificity of this phenomenon remain incompletely defined. This systematic review and meta-analysis examined age-related differences in MPS across post-absorptive, post-prandial, post-exercise, and combined post-prandial/-exercise states in healthy adults. Methods: A systematic literature search was conducted in November 2025 across major databases. Eligible studies compared MPS between young (18–35 years) and older (≥60 years) adults using stable isotope tracer techniques under controlled conditions. Random-effects meta-analyses were conducted for post-absorptive and post-prandial conditions, while post-exercise and combined post-prandial/-exercise findings were synthesized qualitatively due to substantial methodological heterogeneity. Meta-regression explored potential moderators, and risk of bias was assessed using the ROBINS-I tool. Results: Forty-six studies including 1,280 participants (700 older adults, 580 young) met the inclusion criteria. Post-absorptive MPS was significantly lower in older compared with younger adults (SMD = −0.167; 95% CI: −0.313 to −0.021; p = 0.025; I² = 18.4%). Post-prandial MPS was also reduced in older adults (SMD = −0.348; 95% CI: −0.627 to −0.070; p = 0.014; I² = 83.4%), with consistent directionality across sensitivity analyses. Post-exercise (5/8) and combined post-prandial/-exercise (7/9) studies reported no significant age-related difference. Overall risk of bias was low to moderate. Discussion: These findings demonstrate modest but significant reductions in both post-absorptive and post-prandial MPS with aging, consistent with basal and nutrient-related anabolic resistance. However, the preserved MPS response to exercise suggests maintained anabolic potential when appropriate stimuli are provided. Evidence for combined post-exercise MPS remains mixed, with evidence leaning toward a similar response in young and older adults. Standardization of tracer protocols and sex-specific analyses are warranted to refine mechanistic understanding of age-related anabolic heterogeneity.

BACKGROUND: Heart failure with reduced ejection fraction (HFrEF) affects millions worldwide and is characterized by chronic cardiac dysfunction, impaired perfusion, altered skeletal muscle energetics, and, thus, exercise intolerance. Efficient therapeutic strategies reducing the burden of the impaired muscle metabolism in HFrEF are currently lacking. Hence, in the present study, we sought to determine whether myosin dynamics and its important role in ATP consumption can constitute a potent biochemical target to optimize skeletal muscle energy usage in HFrEF. METHODS: We used skeletal muscle tissue from 11 human patients with HFrEF and 10 controls with comparable age, sex, and body mass index. We isolated individual myofibres and incubated them ex vivo with varying concentrations of a myosin inhibitor, mavacamten. We then performed 2′-(or-3′)-O-(N-Methylanthraniloyl) adenosine 5′-triphosphate chase experiments, together with LC/MS-based proteomics profiling. RESULTS: We observed a distinct regulation of acetyl-lysine sites and higher myosin energy consumption in resting muscle fibers from patients with HFrEF than in controls. When exposed to mavacamten, we found a dose-dependent reduction in myosin ATP consumption in myofibres of patients with HFrEF, reversing the pathological over-consumption. CONCLUSIONS: Skeletal muscle myosin becomes inefficient in HFrEF. Pharmacological inhibition of myosin ATPase activity offers an inventive strategy to lower muscle energy demand and potentially address metabolic disturbances in HFrEF.

Myasthenia gravis with muscle-specific kinase antibodies (MuSK-MG) is an autoimmune disorder marked by neuromuscular junction (NMJ) disruption and selective muscle atrophy, yet its intrinsic myocellular mechanisms remain unclear. Using a rat model generated by active immunization with the N-terminal MuSK60 peptide, we characterized muscle pathology, NMJ morphology, and whole-muscle proteome remodeling across anatomically distinct skeletal muscles. Anti-MuSK rats developed seropositivity, body-mass loss, fragmented and denervated NMJs, and pronounced atrophy restricted to slow-twitch/type I fibers, particularly in the soleus muscle. Quantitative proteomics identified extensive muscle-specific alterations, most prominent in soleus, with fewer in diaphragm and sternohyoideus. Gene set enrichment analysis revealed coordinated downregulation of mitochondrial, ribosomal, and myosin-complex proteins in soleus, partial mitochondrial involvement in diaphragm, and compensatory upregulation of translational and proteasomal pathways in diaphragm. Correlation analysis linked soleus mass loss to elevated abundance of ubiquitin-proteasome and calcium-handling proteins, implicating proteolytic and bioenergetic stress mechanisms. The consistent upregulation of NCAM1 and MUSTN1 suggests generalized myocellular responses to MuSK dysfunction. Together, these data demonstrate that MuSK autoimmunity elicits fiber-type–selective atrophy and profound proteome remodeling beyond NMJ impairment, highlighting disrupted mitochondrial and translational homeostasis as central features of the MuSK-MG muscle phenotype.

In this study, the authors reveal that elevated NT-proBNP levels are inversely associated with muscle function and cellular features in patients with chronic heart failure (CHF), including muscle fiber cross-sectional area, muscle stem cell content, and capillarization. NT-proBNP appears to be a more reliable marker than left ventricular ejection fraction (LVEF) for identifying skeletal muscle abnormalities and predicting muscle loss in CHF, offering potential for early intervention and personalized care.

Physical exercise promotes brain health and cognitive function possibly through mechanisms that include strengthened resistance to oxidative stress. However, limited research has explored the cumulative effects of regular voluntary exercise on both oxidative stress and defence mechanisms in hippocampus and cortex, two regions essential for cognitive function. Especially, adaptations in the young, healthy brain are insufficiently understood. This study investigates the impact of 8 weeks of voluntary wheel running on oxidative damage and counteracting defence mechanisms in the cortex and hippocampus of young, healthy female rats. To this end, we assessed oxidative damage to proteins and DNA, antioxidant defence, and DNA repair mechanisms, focusing on the base excision repair pathway. Our findings show that 8 weeks of voluntary exercise does not significantly modify oxidative damage or antioxidant defences in either cortical or hippocampal brain regions. Instead, the voluntary wheel running intervention led to a reduction in the levels of DNA polymerase β and mitochondrial apurinic/apyrimidinic endonuclease 1, key enzymes involved in base excision repair. Moreover, mitochondrial DNA copy number increased in the cortex, but decreased in the hippocampus, suggesting distinct regional adaptations. Collectively, these results indicate that the healthy young brain maintains redox homeostasis despite reduced DNA repair capacity. By analysing a comprehensive array of biomarkers in two brain regions, this study addresses gaps in our current knowledge on prolonged training and brain health and provides valuable insights into how regular exercise produces region‐specific and shared responses in the healthy state.