Alpha and Omega of Lifestyle Therapy (Alpha&Omega)

Alpha and Omega of Lifestyle Therapy - Resistance Training and Ingestion of n-3 Polyunsaturated Fatty Acids to Improve Health and Muscle Functions in Individuals With Obesity and Healthy Controls

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

Intake of 1 gram omega-3 (capsules) per day for 20 weeks + 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)

Intake of 1 gram sunflower oleic oil (capsules) per day for 20 weeks + 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)

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)

Muscle mass of the legs measured as the weighted average of data from ultrasound, MRI, immunohistochemistry and DXA measurements

Maximal cycling performance measured as peak power output (Watt) during an incremental one-legged cycling test

The ability of muscles of the lower body to perform repeated dynamic contractions at a specified submaximal load (70% of 1RM) to exhaustion

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

Expression of genes associated with inflammation and lipid metabolism in peripheral blood mononuclear cell measured using quantitative PCR

Concentrations of various lipids and lipid metabolites such as triglycerides, LDL, HDL, ceramides, dihydroceramides, glucosylceramides, and lactosylceramides measured in serum using tageted metabolomics

Concentrations of nutrients (such as amino acids) and ions (such as iron and calcium) measured in serum

Concentrations of hormones such as testosterone, growth hormone, thyroid hormones, cortisol and insulin (as well as c-peptide) measured in serum

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

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

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

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

RNA (e.g. messenger RNA, ribosomal RNA, microRNA, long non-coding RNA) abundances in subcutaneous fat, measured as targeted genes

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

Health-related quality of life in overweight/obesity individuals measured using The impact of weight on quality of life (IWQOL) questionnaire

Health-related quality of life measured using the Positive and Negative Affect Schedule (PANAS) questionnaire

Activities of daily living (e.g. time spent in physical activity, intensities of activities) measured using questionnaire

Dietary registration measured using a food frequency questionnaire, assessing nutritional composition, energy intake and habitual patterns of dietary intake

Inclusion Criteria: Untrained (less than 2 sessions of resistance exercise per month and less than 3 hours of endurance exercise per week) Exclusion Criteria: Unstable cardiovascular disease Injuries affecting the ability to perform heavy resistance exercise Mental illness Allergy to local anesthesia Smoking Use of medicine or drugs containing steroids the last two months prior to inclusion