Exploring the role of inflammageing, polyunsaturated fatty acids and muscle molecular signaling in sarcopenia.

Sarcopenia is a muscle disease, characterized by loss of muscle mass and function, leading to 'muscle failure'. Primary sarcopenia is age-driven and is a growing concern in the ageing population. It is highly prevalent amongst older adults and can seriously affect the daily life of an older adult, e.g., by limiting the ability to walk and to lift heavy objects like groceries or through difficulties to climb the stairs. One of the major mechanisms behind the onset and progression of sarcopenia is the chronic low grade inflammatory state related with ageing, the so-called 'inflammageing'. However, the exact mechanisms by which inflammageing causes sarcopenia are not completely clear yet. The overall aim of this doctoral project was to gain fundamental insights in the role of inflammageing in the development and treatment of sarcopenia. A special interest was given to the role of omega-3 PUFAs in sarcopenia, since omega-3 PUFAs exert anti-inflammatory properties. Zooming in on their role in sarcopenia can contribute to elucidating the inflammageing-sarcopenia interplay. This doctoral dissertation contains five chapters with omega-3 PUFAs and inflammatory markers at the centre stage. Regarding omega-3 PUFAs, we aimed to investigate the role of omega-3 PUFAs in the prevention and treatment of sarcopenia (chapter 1) as well as to assess in sarcopenic older adults the relationship between PUFAs dietary intake, status and sarcopenia (chapter 2). Regarding inflammatory markers, we aimed to determine in middle-aged and older European men the association between inflammatory markers and sarcopenia (chapter 3), as well as to determine this relationship in sarcopenic older adults (chapter 4). Finally, in chapter 5 we aimed to compare the protein expression profiles in skeletal muscle of older adults with low muscle strength to older adults with preserved muscle strength, in order to explore the inflammageing-sarcopenia interplay at a molecular level. For chapter 2, 4 and 5 of this doctoral project, we used data obtained from the ongoing Exercise and Nutrition for Healthy AgeiNg (ENHANce) study. ENHANce recruits sarcopenic older adults aged 65 years or older and aims to assess the effect of combined anabolic interventions (protein supplement, omega-3 supplement and physical exercise) on physical performance in older adults with sarcopenia, compared to single interventions or placebo in a 5-armed triple-blinded RCT. In view of chapter 3, we used data from the European Male Aging Study (EMAS). EMAS is a population-based prospective cohort study, primarily aiming to examine the influence of hormonal decline on the health of ageing men. Subjects were assessed at baseline (2003-2005) and again after a median follow-up of 4.3 years. In chapter 1, we provided an overview of existing observational and interventional data on omega-3 PUFAs and sarcopenia, as well as some potential working mechanisms. With respect to the underlying working mechanisms, we found that omega-3 PUFAs exert anti-inflammatory effects and might as such counteract the inflammageing that underlies sarcopenia. Moreover, omega-3 PUFAs were shown to improve sarcopenia by reducing insulin resistance and anabolic resistance. In general, we found that observational studies suggested a positive association between dietary intake of omega-3 PUFAs and various sarcopenia-defining parameters, such as handgrip strength, muscle mass, gait speed, and a decreased risk of functional decline in older adults. Some interventional studies included in our review, in which omega-3 PUFAs were supplemented without any other treatment, suggested that their use might improve gait speed, muscle strength and mass in older adults. When combined with exercise, omega-3 PUFAs supplementation was found to increase the effect of resistance training. However, not all observational and interventional studies could confirm the promising findings on the relationship between omega-3 PUFAs and sarcopenia. The existing evidence still has crucial gaps regarding dosage, composition, modality (alone or combined with exercise) and duration of omega-3 PUFAs supplementation in sarcopenia. In chapter 2, we examined the interplay between omega-3 and omega-6 PUFAs dietary intake, status and sarcopenia in older adults with sarcopenia. We found that omega-3 and omega-6 PUFAs intake was below the recommended intake for this population. Moreover, there was no good correlation between dietary intake - assessed with four-day food records - and PUFAs' nutritional status in RBC. When exploring associations of PUFAs intake and status in this population, intake of EPA, DHA and LA were associated with indirect sarcopenia-related traits such as QoL and physical activity (EPA). Nutritional status of ALA (inversely) as well as DHA and its related O3I (positively) correlated with a direct sarcopenia-defining parameter aLM. Additionally, DHA and O3I status were positively associated with QoL measures (SF-36 mental score and SarQoL), whereas EPA and O3I status were associated with physical activity. The objective of chapter 3 was to examine the relationship between inflammatory markers (hs-CRP, WBC and albumin) and sarcopenia or its related traits in middle-aged and older men of the EMAS study. In EMAS participants of Leuven and Manchester (n=447), WBC levels were inversely associated with gait speed, whereas no other significant associations between inflammatory markers and sarcopenia-defining parameters (muscle strength, mass and physical performance) were found. In the analyses with knee extensor muscle strength (n=277), WBC levels were also inversely associated with isometric 90° and isokinetic 60°/S PT/BW. Interestingly, hs-CRP and WBC levels were inversely associated with both physical activity (PASE score) and the physical component score of the SF-36 questionnaire in a large cohort (n = 2577) of the EMAS study. Regarding the longitudinal analyses, baseline levels of hs-CRP, WBC and albumin were not associated with change in handgrip strength, chair stand test, aLM, gait speed, PASE, or SF-36 scores nor with incident sarcopenia, not even in subgroups with chronic inflammation. In chapter 4, we explored the correlation between inflammatory markers (hs-CRP, albumin, IL-1b, IL-6, IL-8 and TNF-a) and sarcopenia-related traits in sarcopenic older adults of the ENHANce study. Contrary to what was expected, our findings suggested a positive correlation of IL-1β levels with handgrip strength and of IL-6 levels with appendicular lean mass, instead of an inverse relationship. On the other hand, step count was - as expected - inversely related with IL-6 levels. Furthermore, our data highlighted a potential role of gender, as the sex-specific analyses in present study revealed altered results compared to the whole study population. In women, IL-1β was positively correlated with handgrip strength and appendicular lean mass, whereas IL-8 was inversely correlated with handgrip strength. In the men included in this study, no significant associations were found with sarcopenia-defining parameters (handgrip strength, chair stand test, aLM, gait speed and SPPB) but only an inverse correlation of pro-inflammatory markers hs-CRP, IL-6 and TNF-α with the SF-36 physical component score, representing physical-related QoL. However, these results need to be interpreted cautiously due to low number of subjects. Finally, in chapter 5 we compared protein expression profiles of the m. vastus lateralis between older adults with low muscle strength and those with preserved muscle strength. In total, muscle biopsy samples of 24 older adults pooled from the ENHANce study and a recent study by Dalle et al. were included (13 with preserved and 11 with low muscle strength). Surprisingly, catabolic signalling (i.e., FOXO1/3a, MuRF1, MAFbx, LC3b, Atg5, p62) was not differentially expressed between both groups, whereas the mitochondrial marker COX-IV, but not PGC1α and citrate synthase, was lower in the low muscle strength group. Stress factors CHOP and p-ERK1/2 were higher (~1.5-fold) in older adults with low muscle strength. In contrast to our expectations, the inflammatory marker p-p65NF-κB was about 7-fold higher in older adults with preserved muscle strength. Moreover, expression of myogenic factors (e.g., Pax7, MyoD, desmin; ~2-fold) was higher in the low muscle strength group. To summarize, whereas the increased stress factors might reflect the age-related deterioration of tissue homeostasis (e.g., due to misfolded proteins), upregulation of myogenic markers in the low strength group might be an attempt to compensate for the gradual loss in muscle quantity and quality. To conclude, the findings of this doctoral dissertation support a potential role of inflammageing in development and treatment of sarcopenia. Moreover, our findings might help to pave a way towards implementation of omega-3 PUFAs in sarcopenia treatment, whilst we await conclusive RCT data in sarcopenic older adults from intervention trials (e.g., from the ENHANce trial). Finally, our findings opened different perspectives for future research in the inflammageing-sarcopenia interplay.

Jaar van publicatie:2022

Toegankelijkheid:Open