The study aims to investigate the effects of double-blinded, randomized placebo-controlled n3-fatty acid supplementation (1000 mg day-1) and 13 weeks of resistance training on muscle function/biology and systemic health in individuals with obesity (BMI\>30) and lean individuals (BMI\<30)
Lifestyle therapy is important for treating lifestyle-related morbidities such as obesity. Such therapy often includes exercise and nutrition, and leads to improved health, functionality and quality of life. Unfortunately, obesity leads to adverse changes in the physiological milieu, including inflammation and altered nutritional status such as reduced omega-3:omega-6 ratios. Indeed, inadequate omega 3 levels are common even among lean individuals. This may negatively affect the outcome of lifestyle therapy with exercise, particularly those involving resistance training, contributing to the large heterogeneity seen in training responses. In accordance with this, many individuals (including both lean and obese subjects) fail to improve muscle biology/functions and health, including failure to increase muscle mass and strength, failure to improve glucose handling and inflammatory status. This makes general lifestyle therapy recommendations ineffective. Here, we investigate effects of double-blinded, randomized placebo-controlled n3-fatty acid supplementation (1000 mg day-1) and 13 weeks of low- and high-load resistance training on muscle growth/function/biology and health in individuals with obesity (BMI\>30, n=60) and lean controls (BMI\<30, n=60). Each participant will perform two different training protocols, one on each leg. The supplement period will commence 7 weeks prior to the onset of the strength training intervention to ensure adequate omega-3 biology at the onset of training. Analyses include assessment of the separate and combined effects of n3-supplementation and obesity on training responses to resistance training, measured as muscle mass, muscle strength/functionality, muscle biological traits, and systemic health variables such as hormone/inflammation/glucose biology, adipose tissue biology/mass, gut microbiome and health-related quality of life. The project will provide important insight into the feasibility of resistance training and n-3 fatty acid supplementation for treating individuals with obesity, paving the way for personalized lifestyle therapy. The study has two defined main outcome measures, targeting the combined effects of omega-3 and strength training on i) muscle thickness of the thigh (measured using ultrasound; this main outcome measure targets the effects of the intervention on muscle growth), and ii) glucose tolerance (measured using an oral glucose test; this main outcome measure targets the effects of the intervention on improvements in health). In our analytical approach, we will use a mixed model-approach to assess the main effects of the intervention, mainly defined as changes from before to after the resistance training intervention. Importantly, for health variables such as glucose tolerance, analyses will be performed by accounting for individual variation at baseline, as any beneficial effect can be expected to be higher/present only in individuals with a pathological/diseased starting point. Notably, for many variables, we will collect data from two additional time points (pre-supplementation and after two weeks of familiarization to training). These data will provide insight into additional perspectives, such as the effects of omega-3 intake-only on glucose tolerance, which will bring additional depth to our conclusions (these analyses are not necessarily specified in the Outcome Measures section). For other data, such as primary cultivation of skeletal muscle and muscle mitochondrial respiration, data will only be collected from a randomized subset of participants. For analyses of the effects of the intervention on obesity-related pathophysiologies and health-related quality of life, data from a group of non-intervention individuals will act as reference values (data sampled alongside the intervention). Finally, we will use regression analyses to explain individual differences in training responses, with particular emphasis on muscle hypertrophy/glucose tolerance and their mechanistic origin of nature. 2021/08: The number of anticipated participants was increased from 120 to 150 due to circumstances relating to the SARS-CoV-2 pandemic
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
QUADRUPLE
Enrollment
150
High-load and low-load resistance exercise two times per week for 10 weeks, preceded by 3 weeks of familiarization to training (high-load training)
1 gram of omega-3 per day for 20 weeks
1 gram of sunflower oleic oil per day for 20 weeks
Inland Norway University of Applied Sciences
Lillehammer, Norway
Muscle thickness, ultrasound
Muscle thickness of vastus lateralis and vastus intermedius measured using ultrasound
Time frame: Changes from before to after the resistance training intervention (week 8 to 20)
Glucose tolerance
Glucose tolerance measured using an oral glucose tolerance test
Time frame: Changes from before to after the resistance training intervention (week 8 to 20)
Lean body mass
Lean body mass measured using whole-body DXA scan
Time frame: Changes from before to after the resistance training intervention (week 8 to 20)
Fat mass
Fat mass measured using whole-body DXA scan
Time frame: Changes from before to after the resistance training intervention (week 8 to 20)
Visceral fat mass
Visceral fat mass measured using whole-body DXA scan
Time frame: Changes from before to after the resistance training intervention (week 8 to 20)
Muscle mass, MRI
Thigh muscle cross sectional area/volume measured using magnetic resonance imaging (MRI)
Time frame: Changes from before to after the resistance training intervention (week 8 to 20)
Muscle mass, immunohistochemistry
Fibre type-specific muscle-fibre cross-sectional area measured using immunohistochemistry
Time frame: Changes from before to after the resistance training intervention (week 8 to 20)
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Muscle mass, combined measure
Muscle mass of the legs measured as the weighted average of data from ultrasound, MRI, immunohistochemistry and DXA measurements
Time frame: Changes from before to after the resistance training intervention (week 8 to 20)
Muscle fibre type composition
Muscle fibre type composition measured using immunohistochemistry
Time frame: Changes from before to after the resistance training intervention (week 8 to 20)
Myonuclear number
Fiber type-specific myonuclear number measured using immunohistochemistry
Time frame: Changes from before to after the resistance training intervention (week 8 to 20)
Muscle satellite cell number
Fiber type-specific muscle satellite cell number measured using immunohistochemistry
Time frame: Changes throughout the course of the resistance training intervention (weeks 8, 10 and 20)
Muscle capillarization
Fiber type-specific muscle capillarization measured using immunohistochemistry
Time frame: Changes from before to after the resistance training intervention (week 8 to 20)
Fat infiltration (muscle)
Fat infiltration in thigh muscle measured using magnetic resonance imaging (MRI)
Time frame: Changes from before to after the resistance training intervention (week 8 to 20)
Muscle quality
Muscle strength measured per muscle mass of the legs
Time frame: Changes from before to after the resistance training intervention (week 8 to 20)
Unilateral lower body maximal strength
The ability of muscles of the lower body to exert maximal force during dynamic movements
Time frame: Changes throughout the course of the resistance training intervention (weeks 8, 10 and 20)
Unilateral lower body isokinetic muscle strength
The ability of the knee extensors to exert maximal force during isokinetic movements
Time frame: Changes throughout the course of the resistance training intervention (weeks 8, 10 and 20)
Unilateral lower body isometric muscle strength
The ability of the knee extensors to exert maximal force during isometric actions
Time frame: Changes throughout the course of the resistance training intervention (weeks 8, 10 and 20)
Peak power output during one-legged cycling
Maximal cycling performance measured as peak power output (Watt) during an incremental one-legged cycling test
Time frame: Changes from before to after the resistance training intervention (week 8 to 20)
Oxygen consumption during one-legged cycling
The ability to consume oxygen during an incremental one-legged cycling test
Time frame: Changes from before to after the resistance training intervention (week 8 to 20)
Unilateral lower body muscle endurance
The ability of muscles of the lower body to perform repeated dynamic contractions at a specified submaximal load (70% of 1RM) to exhaustion
Time frame: Changes throughout the course of the resistance training intervention (weeks 8, 10 and 20)
Waist circumference
Circumference of the waist measured using measuring tape
Time frame: Changes from before to after the resistance training intervention (week 8 to 20)
Blood pressure at rest
Blood pressure at rest measured using an automated upper-arm blood pressure cuff
Time frame: Changes from before to after the resistance training intervention (week 8 to 20)
Hemoglobin glycosylation (HbA1c)
Long-term glucose levels measured as hemoglobin glycosylation of the metabolic syndrome such as waist circumference, blood pressure at rest, lipid profile ( hemoglobin glycosylation (HbA1c) and fasting blood glucose
Time frame: Changes throughout the course of the intervention (weeks 0, 8 and 20)
Fasting blood glucose
Fasting blood glucose measured in serum
Time frame: Changes throughout the course of the intervention (weeks 0, 8 and 20)
N-3 PUFA (blood)
Omega-3 (DHA/EPA) levels in blood
Time frame: Changes throughout the course of the intervention (weeks 0, 8 and 20)
Inflammatory characteristics of peripheral blood mononuclear cell (PBMC)
Expression of genes associated with inflammation and lipid metabolism in peripheral blood mononuclear cell measured using quantitative PCR
Time frame: Throughout the course of the intervention (weeks 0, 8 and 20)
Lipid concentrations in blood
Concentrations of various lipids and lipid metabolites such as triglycerides, LDL, HDL, ceramides, dihydroceramides, glucosylceramides, and lactosylceramides measured in serum using tageted metabolomics
Time frame: Changes throughout the course of the intervention (weeks 0, 8 and 20)
Nutritent concentrations in blood
Concentrations of nutrients (such as amino acids) and ions (such as iron and calcium) measured in serum
Time frame: Changes throughout the course of the intervention (weeks 0, 8 and 20)
Hormone concentrations in blood
Concentrations of hormones such as testosterone, growth hormone, thyroid hormones, cortisol and insulin (as well as c-peptide) measured in serum
Time frame: Changes throughout the course of the intervention (weeks 0, 8 and 20)
Concentrations of inflammatory factors in blood
Levels of inflammatory factors such as IL6, CRP and NFkB in serum
Time frame: Changes throughout the course of the intervention (weeks 0, 8 and 20)
Muscle fractional synthesis rate
Protein/RNA synthesis rate measured using heavy water (deuterium) and chromatography/spectrometry
Time frame: Week 18 to 20
Gene expression in skeletal muscle (intervention)
RNA (e.g. messenger RNA, ribosomal RNA, microRNA, long non-coding RNA) abundances in m. vastus lateralis, measured both as targeted genes and at the level of the transcriptome
Time frame: Changes from before to after the resistance training intervention (week 8 to 20)
Gene expression in skeletal muscle (familiarization)
RNA (e.g. messenger RNA, ribosomal RNA, microRNA, long non-coding RNA) abundances in m. vastus lateralis, measured both as single genes and at the level of the transcriptome
Time frame: Changes from before to after familiarization to resistance exercise (week 8 to 10)
Protein abundance in skeletal muscle (intervention)
Levels of proteins and their modification status (e.g. phosphorylation) in m. vastus lateralis, measured at the level of single proteins and at the level of the proteome
Time frame: Changes from before to after the resistance training intervention (week 8 to 20)
Protein abundance in skeletal muscle (familiarization)
Levels of proteins and their modification status (e.g. phosphorylation) in m. vastus lateralis, measured at the level of single proteins and at the level of the proteome
Time frame: Changes from before to after the resistance training intervention (week 8 to 10)
Mitochondrial functions in muscle
The ability of muscle mitochondria (extracted from muscle homogenate) to synthesize ATP in vitro
Time frame: Changes from before to after the resistance training intervention (week 8 to 20)
Gene expression in subcutaneous fat
RNA (e.g. messenger RNA, ribosomal RNA, microRNA, long non-coding RNA) abundances in subcutaneous fat, measured as targeted genes
Time frame: Changes from before to after the resistance training intervention (week 8 to 20)
Satellite cell proliferation and myotube growth (in vitro)
The ability of muscle satellite cells (extracted from muscle homogenate) to proliferate (rates of cell division), differentiate into myotubes and subsequently grow (rates of change in myotube size) in primary cultures
Time frame: Changes from before to after N3-supplementation-only (week 0 to 8)
Musculoskeletal pain (Nordic Pain Questionnaire)
Musculoskeletal pain measured using The standardized Nordic Pain Questionnaire
Time frame: Changes throughout the course of the training intervention (weeks 0, 8 and 20)
Musculoskeletal pain (VAS)
Musculoskeletal pain measured using VAS-scale (1-10)
Time frame: Changes throughout the course of the training intervention (weeks 0, 8 and 20)
Gastrointestinal symptoms
Gastrointestinal symptoms such as abdominal discomfort and pain, measured using Rome IV criteria
Time frame: Changes throughout the course of the training intervention (weeks 0, 8 and 20)
Gut microbiome (feces, N3-supplementation-only)
Relative composition of the gut microbiome measured using quantitative polymerase chain reaction
Time frame: Changes from before to after N3-supplementation-only (week 0 to 8)
Gut microbiome (feces, training intervention)
Relative composition of the gut microbiome measured using quantitative polymerase chain reaction
Time frame: Changes from before to after the resistance training intervention (week 8 to 20)
Fecal short-chained fatty acids (N3-supplementation-only)
Short chained fatty acids measured in feces
Time frame: Changes from before to after N3-supplementation-only (week 0 to 8)
Fecal short-chained fatty acids (training intervention)
Short chained fatty acids measured in feces
Time frame: Changes from before to after the resistance training intervention (week 8 to 20)
Arterial stiffness
Arterial stiffness measured using pulse-wave velocity
Time frame: Throughout the course of the intervention (week 0, 8 and 20)
Health-related quality of life (SF-36)
Health-related quality of life measured using the SF-36 questionnaire
Time frame: Changes throughout the course of the intervention (week 0, 8 and 20)
Health-related quality of life in overweight/obesity
Health-related quality of life in overweight/obesity individuals measured using The impact of weight on quality of life (IWQOL) questionnaire
Time frame: Changes throughout the course of the intervention (week 0, 8 and 20)
Health-related quality of life (PANAS)
Health-related quality of life measured using the Positive and Negative Affect Schedule (PANAS) questionnaire
Time frame: Changes throughout the course of the intervention (week 0, 8 and 20)
Activities of daily living
Activities of daily living (e.g. time spent in physical activity, intensities of activities) measured using questionnaire
Time frame: Changes throughout the course of the intervention (week 0, 8 and 20)