Regular screening and early intervention, particularly

The gap

Evidence profile

Sourced from the stated research gap and limitations and future work of the source papers, classified as general, drawn from work published between 2024 and 2026, spanning 3 journals. Those papers have been cited 65 times in total.

Supporting evidence — 3 representative gaps

• Correlation between oxidative stress and inflammation with metabolomics profile in skeletal muscle of ageing animal model and its modulation by tocotrienol-rich fraction (2026) · British Journal of Biomedical Science · doi

  There is a need for regular screening and early intervention, particularly among high-risk groups such as older adults and individuals with comorbid conditions. There is a lack of understanding of the correlation between oxidative stress and inflammation with the metabolomics profile in ageing skeletal muscle.

  generalstated research gap
  Keywords: there need regular screening early intervention particularly among
• Mitochondrial calcium uptake declines during aging and is directly activated by oleuropein to boost energy metabolism and skeletal muscle performance (2024) · Cell Metabolism · cited 65× · doi

  Convergent evidence demonstrates that mitochondrial calcium uptake declines during aging and sarcopenia in mice and humans. Although MCUR1 expression was reduced in muscle biopsies of sarcopenic male patients from Singapore in the retrospective Multi-Ethnic Molecular determinants of Sarcopenia (MEMOSA) cohort,15 one limitation of our work is that functional quantification of mitochondrial calcium uptake was performed in ex vivo primary human muscle cells but could not be performed directly in human muscle biopsies as this requires a prospective study with ex vivo analysis in living, dissociated myofibers. Replication of these findings and expansion across genders in different human aging cohorts, where sarcopenia may arise from different genetic and environmental origins, will be important. To this end, the Study of Muscle, Mobility and Aging (SOMMA) US cohort that analyzed muscle biopsies and mitochondrial bioenergetics in relation to muscle function, frailty, and quality of life in older men and women from the US will be of particular interest.71 Another limitation arises from the fact that metabolic homeostasis and physio-pathological decline during aging are multi-factorial and involve crosstalk between different organs. Although our genetic and nutritional experiments demonstrated a causal role for muscle MCUR1 decline during sarcopenia and a requirement for muscle MCU for oleuropein-induced phenotypes, oleuropein may also affect other organs, and the impact on systemic metabolism, such as VO2max and substrate utilization, will deserve further investigation. Moreover, other mechanisms can contribute to impaired mtCa2+ uptake, mitochondrial dysfunction, and, more generally, to the regulation of muscle mass and function during sarcopenia. Although oleuropein is a promising nutritional solution for the management of sarcopenia, oleuropein supplementation should be coupled to a holistic approach combining physical activity and healthy nutrition with adequate protein and vitamin D intake to overcome the multi-factorial nature of age-related muscle decline. and collaborator Professor Lillycrop and honor her memory through this work. K.M.G. is a guarantor for her contribution to experiments and drafting of the manuscript. The study received internal and external funding by Socie´ te´ des Produits Nestle´ SA. C.M. received funding from the French Muscular Dystrophy Association (22493 and 24863), the Italian Ministry of University and Research (PRIN 2022B32SCL), and the Italian Veneto Region (POR FESR). R.R. received funding from the Italian Ministry of Research (PRIN 2020R28P2E), the Italian Ministry of Health (RF-2016-02363566), the University of Padova (Stars 2017), the Italian Cariparo Foundation, the Italian Telethon Association (GGP16029), and the Italian Cancer Research Association. C.M. and R.R.

  generallimitationsevidence 5/5
  Keywords: muscle italian sarcopenia mitochondrial aging received funding biopsies multi human different decline oleuropein association ministry
• Shared mechanisms of musculoskeletal dysfunction in type 2 diabetes mellitus: Insights into future therapeutic directions (Review) (2026) · International Journal of Molecular Medicine · doi

  Critical appraisal of the evidence, knowledge gaps and future directions. Although the preceding sections summarize the proposed mechanisms underlying diabetes‑related musculo‑ skeletal disorders, the strength of evidence supporting each pathway warrants critical evaluation. Much of the available evidence, particularly for AGEs‑RAGE signaling and chronic inflammation, comes from in vitro and animal studies. Therefore, its direct translation to human pathophysiology should be interpreted with caution. For instance, AGE accu‑ mulation is consistently associated with increased tendon stiffness and reduced elasticity in rodent models. However, evidence from human studies is largely correlative and is often confounded by disease duration and comorbidities (22,52,216). Likewise, mitochondrial dysfunction is considered a central feature of numerous proposed mechanisms. However, current evidence mainly comes from associative studies showing reduced oxidative capacity and abnormal mitochondrial morphology in diabetic muscle (14,178). Whether these mitochondrial alterations initiate insulin resistance or arise as a consequence of the diabetic metabolic milieu remains unresolved (264). Notable contradictions exist within literature. For example, although chronic hyperglycemia is widely accepted to impair angiogenesis, some studies report elevated VEGF levels in diabetic tissues such as the retina. This finding suggests a paradoxical upregulation in response to hypoxia under certain pathological conditions (103,104). By contrast, peripheral tissues such as skeletal muscle and tendon exhibit reduced VEGFR2 signaling and poor neovascularization (115,118,119). These observations suggest that the overall angiogenic response depends on the complex interplay of multiple dysregulated pathways and may be tissue dependent. A significant knowledge gap remains in the understanding of the ΤΒΙ. While the role of TGF‑β1 in fibrosis is well‑established, the precise molecular triggers that shift tissue repair from regenerative fibrocartilage formation to pathological scarring in diabetes remain largely unknown (244,265). In addition, the specific contributions of different immune cell subpopulations, particularly the dynamic phenotypic switching of macrophages, remain incompletely understood. Most available evidence comes from a limited number of studies. Finally, most current evidence is derived from single‑tissue or single‑mechanism studies, making it difficult to understand the integrated, system‑level response to diabetes. Future research should prioritize longitudinal human studies, apply multi‑omics approaches to capture the complexity of the disease, and develop experimental models that simultaneously investigate interactions among skeletal muscle, tendon, bone and their interfaces. Such integrative approaches will facilitate the identification of robust thera‑ peutic target

  generalfuture workevidence 5/5
  Keywords: evidence diabetes skeletal comes human tendon reduced mitochondrial diabetic muscle response tissue critical knowledge future

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