Biology subjects

Cefis, M.

Publications and source records attributed to Cefis, M..

5 recordsLinked to original sources

bioRxiv2026

Serum C-terminal agrin fragment as a biomarker of age-related neuromuscular decline in men: influence of physical activity

Aging is accompanied by progressive neuromuscular junction (NMJ) degeneration. The C-terminal agrin fragment (CAF), a circulating product of agrin cleavage, has been proposed as a minimally invasive biomarker of NMJ degradation, but its relationships with neuromuscular and functional characteristics, and the influence of physical activity, remain underexplored. We studied 136 community-dwelling men aged 20-92 years (active, n=87; inactive, n=49). Serum CAF was measured by ELISA. The proportion of NCAM-positive fibers, a marker of myofiber denervation, was assessed in vastus lateralis biopsies (n=127). Neuromuscular outcomes included maximal voluntary isometric contraction (MVIC), lower-limb power, electromechanical delay (EMD), nerve conduction velocities, H/M ratio, central activation ratio, co-activation, and twitch characteristics. Functional capacity was assessed using the 6-minute walk test, alternating step test, Timed Up and Go, sit-to-stand tests, and fast gait speed. Serum CAF increased with age and was positively associated with NCAM-positive fiber proportion. Higher CAF was associated with lower MVIC, lower-limb power and poorer performance on all functional tests. CAF was associated with longer EMD in the overall cohort and in inactive men only, and with a lower H/M ratio in inactive men. No associations were found with nerve conduction velocities, central activation ratio, co-activation, or twitch amplitude. Active men had lower CAF levels than inactive men, particularly after age 70. Serum CAF is associated with age-related declines in neuromuscular and functional capacity and with NCAM-positive fiber prevalence, supporting its utility as an accessible biomarker of NMJ remodeling. Physical activity was associated with a more favorable CAF profile in older men.

physiology↗

bioRxiv2025

Parkin overexpression attenuates muscle atrophy and improves mitochondrial bioenergetics but fails to improve key histological features in a mouse model of Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy (DMD) is the most common childhood muscular disorder. Mitochondrial dysfunctions are key disease features of the disease, and strategies that improve mitochondrial health have emerged as promising to slow disease progression. Emerging evidence indicates that impaired/insufficient mitophagy may contribute to the accumulation of mitochondrial dysfunction seen in patients and animal models of DMD. We therefore hypothesized that overexpressing Parkin, a key mitophagy regulator, may improve mitochondrial and muscle health in a mouse model of DMD. To this end, Parkin was overexpressed using intramuscular injections of adeno-associated viruses performed in 5-week-old and 18-week-old D2.B10-Dmdmdx/J mice (D2.mdx), a widely used mouse model of DMD. Four and 16 weeks of Parkin overexpression initiated in 5-week-old and 18-week-old D2.mdx, respectively, resulted in muscle hypertrophy, as indicated by an increase in muscle mass and fiber cross-sectional area. While Parkin overexpression did not impact maximal mitochondrial respiration or mitochondrial content, it increased the Acceptor Control Ratio, an index of mitochondrial bioenergetic efficiency. Parkin overexpression also decreased mitochondrial H2O2 emission, a surrogate for mitochondrial ROS production. However, Parkin overexpression failed to reduce the proportion of fibers with central nuclei and markers of muscle damage and/or necrosis. Taken all together, our results indicate that Parkin overexpression can attenuate muscle atrophy, improve mitochondrial bioenergetics and lower mitochondrial ROS production in a mouse model of DMD. These findings showcase the partial beneficial effects of overexpressing Parkin in ameliorating some, but not all, pathological features observed in a mouse model of DMD. Graphical abstractImpact of AAV-mediated Parkin overexpression on Duchenne Muscular Dystrophy (DMD) progression in skeletal muscle of D2.mdx (a mouse model of DMD). Parkin overexpression attenuated muscle atrophy, reduced mitochondrial H2O2 emissions and improved an index of mitochondrial coupling efficiency. Created with BioRender.com. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=179 SRC="FIGDIR/small/659533v3_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@143f08borg.highwire.dtl.DTLVardef@16543a9org.highwire.dtl.DTLVardef@13d1110org.highwire.dtl.DTLVardef@2b5e2e_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2024

Impact of physical activity on physical performance, mitochondrial bioenergetics, ROS production and calcium handling across the human adult lifespan

Aging-related muscle atrophy and weakness contribute to loss of mobility, falls and disability. Mitochondrial dysfunction is widely considered a key contributing mechanism to muscle aging. However, mounting evidence position physical activity as a confounding factor, making unclear whether muscle mitochondria accumulate bona fide defects with aging. To disentangle aging from physical activity-related mitochondrial adaptations, we functionally profiled skeletal muscle mitochondria in 51 inactive and 88 active men aged 20-93. Physical activity status conferred partial protection against age-related decline in physical performance. A trend for reduced muscle mitochondrial respiration with aging was observed in inactive but not in active participants, indicating that aging per se does not alter mitochondrial respiratory capacity. Mitochondrial reactive oxygen species (ROS) production was unaffected by aging and active participants displayed higher ROS production. In contrast, mitochondrial calcium retention capacity decreased with aging regardless of physical activity status and correlated with muscle mass, performance and the stress-responsive metabokine GDF15. Targeting mitochondrial calcium handling may hold promise for treating aging-related muscle impairments.

cell biology↗

bioRxiv2024

Dysregulated Skeletal Muscle Myosin Super-relaxation in Type II, but Not Type I, Diabetes Mellitus

Disrupted energy balance is critical for the onset and development of Type II diabetes. The exact underlying metabolic mechanisms remain incomplete but skeletal muscle is thought to play an important pathogenic role. As the super-relaxed state of its most abundant protein, myosin, regulates cellular energetics, here, we aimed to investigate whether it is altered in patients with type II diabetes. For that, we used vastus lateralis biopsy specimens (obtained from patients with type II diabetes and matched controls) and run a combination of structural and functional assays consisting of loaded Mant-ATP chase experiments, X-ray diffraction and LC-MS/MS proteomics in isolated muscle fibres. Our studies revealed a greater muscle myosin super-relaxation and decreased cellular ATP demand in patients than controls. Subsequent proteomic analyses indicated that these (mal)adaptations likely originated from remodeled sarcomeric proteins and greater myosin glycation levels in patients than controls. Overall, our findings emphasize a complex molecular dysregulation of myosin super-relaxed state and energy consumption in type II diabetes. Ultimately, pharmacological targeting of myosin could benefit skeletal muscle and whole-body metabolic health through the enhancement of ATP consumption. Significance StatementMyosin super-relaxation, essential for the regulation of skeletal muscle metabolic rate, is disrupted in type II diabetes due to protein hyper-glycation. As a consequence, myosin ATP demand is significantly lowered. Overall, our findings provide a strong rationale for the use of activators of myosin ATPase to enhance basal energy expenditure in type II diabetes.

cell biology↗

bioRxiv2021

Role of autophagy in sepsis-induced skeletal muscle dysfunction, whole-body metabolism, and survival

Septic patients frequently develop skeletal muscle wasting and weakness, resulting in severe clinical consequences and adverse outcomes. Autophagy is a stress-induced degradative process essential to cell survival. Recent studies have demonstrated that sepsis triggers sustained induction of autophagy in skeletal muscles, although the impact of this enhanced autophagy on sepsis-induced muscle dysfunction remains unclear. Atg7 is an autophagy gene that plays a major role in autophagosome formation. Using an inducible and muscle-specific Atg7 knockout mouse model (Atg7iSkM-KO), we investigated the functional importance of skeletal muscle autophagy in sepsis. Sepsis was induced using cecal ligation and perforation (CLP) with a sham operation serving as a control. Atg7iSkM-KO mice exhibited a more severe phenotype in response to sepsis, marked by severe muscle wasting and contractile dysfunction, hypoglycemia, higher ketone levels and a decreased in survival as compared to mice with intact Atg7. Several genes that encode 26S proteasome subunits were upregulated, suggesting that activation of the ubiquitin-proteasome system is responsible for the severe muscle atrophy that was seen in these mice. Sepsis and Atg7 deletion resulted in the accumulation of mitochondrial dysfunction, although sepsis did not further worsen mitochondrial dysfunction in Atg7iSkM-KO mice. Overall, our study demonstrates that autophagy inactivation in skeletal muscles triggers significant worsening of sepsis-induced contractile and metabolic dysfunctions and negatively impacts survival. Induction of autophagy in skeletal muscles in response to sepsis thus represents a protective mechanism.

cell biology↗