The impact of vitamin D3 supplementation, chronic obstructive pulmonary disease and exercise load on resistance training-associated adaptations in older adults
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Background: Lifestyle therapy with resistance training is a potent measure to counteract age-related loss in muscle strength and mass. Unfortunately, many individuals fail to respond in the expected manner to such treatment. This phenomenon is particularly common among older adults and those with chronic diseases such as chronic obstructive pulmonary disease (COPD) and may involve endocrine characteristics such as low vitamin D status and low-grade inflammation, as well as suboptimal training protocols. Aims: The Granheim COPD Study consisted of two studies; a preparatory study and a RCT study. COPD is associated with impaired cardiorespiratory capacity, but it remains uncertain if this affects muscular performance. Therefore, in the preparatory study, the aim was to compare muscular performance in three resistance exercises of the legs involving different amounts of active muscle mass in COPD and healthy control (Healthy) persons (Paper I). In the RCT study, the aim was to investigate the effects of 12 weeks of vitamin D3 supplementation-only, followed by 13 weeks of combined vitamin D3 supplementation and resistance training, on muscle functional and biological training-associated adaptations in a mixed group of older adults, and also to compare the muscle functional and biological effects of resistance training for COPD and Healthy, as well as high-load vs low-load resistance training (Paper II-IV). Participants and methods: In the preparatory study, 11 COPD (GOLD grade II/III; forced expiratory volume in first second (FEV1), 53±14% of predicted value; age 66±8 years) and 12 Healthy (FEV1, 117±12% of predicted value; age 62±7 years) participants performed tests of muscular performance in three resistance exercises with different complexity and physiological demand; (i) one-legged knee extension, (ii) one- and (iii) two-legged leg press. In the RCT study, 95 older individuals (56-77 years) were randomly assigned to receive either vitamin D3 or placebo supplementation, stratified by health status (COPD, n=24; Healthy, n=71) and sex. The intervention was initiated by 12 weeks of supplementation-only (two weeks with 10 000 international units (IU) vitamin D3 .day-1, thereafter 10 weeks with 2 000 IU.day-1), followed by 13 weeks of combined supplementation (2 000 IU.day-1) and supervised whole-body resistance training (twice weekly). In the training sessions, leg exercises were performed unilaterally, with one leg randomized to high-load training (10 repetitions maximum; RM) and the contralateral leg randomized to low-load training (30RM). This unilateral training protocol served two purposes: i) to circumvent issues relating to conduction of training with two-legged exercises and ii) to investigate the relative efficacy of two different training modalities. Outcome measures included multiple assessments of muscle strength (nvariables=7), endurance performance (nvariables=6), muscle mass (nvariables=2), muscle quality, muscle biology (m. vastus lateralis; muscle fiber characteristics, RNA content including transcriptome) and health-related variables (body composition, lung function, blood, health-related quality of life). For a subset of participants (COPD, n=11; Healthy, n=12), outcome measures also included mitochondrial quantity (citrate synthase activity) and respiratory capacity. For core outcome domains (muscle strength/mass/quality and lower-limb/whole-body endurance performance), weighted combined factors were calculated from the range of singular assessments. Main results: In the preparatory study, muscular performance was impaired for COPD in two-legged leg press compared to Healthy, but not in one-legged leg press, suggesting that the cardiorespiratory limitations inherent to the disease seems to negatively influence the performance in resistance exercises involving larger amounts of active muscle mass (>one-legged leg press) (Paper I). In the RCT study, 13 weeks of resistance training increased muscle strength (13%), muscle mass (9%) and endurance performance (one-legged, 23%; whole-body, 8%), assessed as weighted combined factors, and were associated with beneficial changes in health variables (e.g. visceral fat, -6%; lowdensity lipoprotein levels, -4%) and muscle tissue characteristics such as muscle fiber type proportions (e.g. IIX, -3%-points), myonuclei·fiber-1 (30%), total RNA/rRNA abundances (15%/6-19%), and transcriptome profiles (e.g. 312 differentially expressed genes). Vitamin D3 supplementation did not affect training-associated changes for any of the main outcome domains, despite robust increases in serum 25(OH)D levels (Δ49% vs placebo) (Paper II). In secondary analyses, resistance training with vitamin D3 supplementation resulted in higher expression of gene sets involved in vascular functions in muscle tissue and larger strength gains in participants with high fat mass, compared to resistance training-only (Paper II). In the RCT study, COPD participants displayed wellknown disease-related pathophysiologies compared to Healthy at baseline, including impaired lung function, higher levels of systemic low-grade inflammation (serum c-reactive protein levels), lower muscle mass and functionality, and muscle biological aberrancies such as lower mitochondrial oxidative capacity, higher proportions of muscle fiber type IIA and IIX and genome-wide differences in transcriptome profiles (differential mRNA expression of 227 genes) (Paper III-IV). However, despite these adversities, COPD participants showed similar or larger improvements to resistance training for health and muscle functional and biological variables compared to Healthy (Paper III-IV). 10RM and 30RM training were associated with similar ratings of perceived exertion. When combining the data from the two study clusters (i.e. COPD and Healthy), 30RM training led to more pronounced increases in lower-body muscle mass compared to 10RM, while 10RM training led to a larger fiber type conversion from IIX to IIA and larger improvements in cycling economy compared to 30RM, but this was not associated with differential changes in muscle strength and muscle performance between the two exercise modalities. Furthermore, 10RM resistance training was associated with improved ability to maintain bone mineral density compared to 30RM resistance training. Conclusions: Vitamin D3 supplementation did not affect muscular responses to resistance training. This rejects the notion that vitamin D3 supplementation is necessary to obtain adequate muscular responses to resistance training in the general older population, at least for the enrolled clusters of COPD and Healthy participants with mostly sufficient vitamin D levels at pre-RCT. Although COPD participants showed clear functional and biological deviations compared to Healthy at baseline, which previously has been speculated to be associated with impaired training responsiveness, they did not show such impaired responses to resistance training in this training setting. Generally, lowload resistance training was associated with larger lower-body muscle mass gains and similar muscle strength and performance improvements compared to high-load resistance training, and can therefore be advocated as an effective resistance training modality alternative for older adults. Importantly, the beneficial effects of high-load resistance training on bone health, emphasizes that resistance training programs for this population should include elements of such training. In general, the training intervention was associated with pronounced health effects, emphasizing the potency of resistance training for preventing/relieving sarcopenia in the general older population and for improving COPD-specific pathophysiologies.
Avhandling (doktorgrad) - Norges idrettshøgskole, 2021
Består avPaper I: Mølmen KS*, Evensen Thy J*, Thallaug Dalane S, Ellefsen S, Falch GS. Muscular performance decreases with increasing complexity of resistance exercises in subjects with chronic obstructive pulmonary disease. Transl Sport Med. 2020;3(1):26-33.
Paper II: Mølmen KS, Hammarström D, Pedersen K, Lie ACL, Steile RB, Nygaard H, Khan Y, Hamarsland H, Koll L, Hanestadhaugen M, Eriksen AL, Grindaker E, Whist JE, Buck D, Ahmad R, Strand TA, Rønnestad BR, Ellefsen S. Vitamin D3 supplementation does not enhance the effects of resistance training in older adults. J Cachexia Sarcopenia Muscle. 2021; published online ahead of issue publication (doi: 10.1002/jcsm.12688).
Paper III: Mølmen KS, Hammarström D, Falch GS, Grundtvig M, Koll L, Hanestadhaugen M, Khan Y, Ahmad R, Malerbakken B, Rødølen TJ, Lien R, Rønnestad BR, Raastad T, Ellefsen S. Chronic obstructive pulmonary disease does not impair responses to resistance training. In review.
Paper IV: Oberholzer L*, Mølmen KS*, Hammarström D, Falch GS, Lundby A-KM, Rønnestad BR, Ellefsen S**, Lundby C**. Resistance exercise training increases skeletal muscle mitochondrial respiration in COPD. Submitted.