Smith, Cassandra (2022) Uncovering the interaction between bone and muscle in older adults: effects of exercise. PhD thesis, Victoria University.

Abstract

Ageing is characterised by a simultaneous loss of muscle mass, strength and physical performance (sarcopenia) and bone mass (osteoporosis). These changes in muscle and bone can lead to reduced physical function, increased falls and fractures and a poorer quality of life. Due to the ageing population and increases in sedentary behaviours, sarcopenia and osteoporosis prevalence and associated burdens are predicted to rise. The simultaneous loss of muscle and bone raised the hypothesis that bone and muscle are not only linked anatomically, but also metabolically and chemically. However, it is still not clear how bone-derived factors are involved in this crosstalk. Bone is an endocrine organ, releasing hormones affecting distant tissues and organs. Osteocalcin (OC) is the most abundant non-collagenous protein in bone. Its total serum levels (tOC) are used clinically as a bone turnover marker (BTM). The undercarboxylated form of OC (ucOC) is considered bio-active, involved in energy metabolism and possibly muscle mass maintenance and strength, at least in rodents. Evidence from human studies is limited and contradictory, in part because most research has focused on tOC, rather than the ucOC. Exercise improves muscle and bone mass, as well as muscle strength, while inactivity has deleterious effects on both organs. Consequently, exercise is a cornerstone approach to maintain and preserve musculoskeletal health in adults, and can be used as a tool to investigate bone-muscle crosstalk. The primary aim of this PhD thesis was to identify the normal range of ucOC across the adult human lifespan, and to explore whether ucOC and other BTMs are related to muscle mass, strength and physical performance. I also explored whether acute exercise can affect the relationships between ucOC and muscle function (strength and physical performance) in older adults. The specific aims were: Study 1: to develop age-based reference ranges for OC and its forms and ratios in healthy adult men. Overall, 236 adult men participated in the study (18 to 92 years old). Serum samples were analysed for tOC and ucOC (using the hydroxyapatite binding method) and carboxylated OC (cOC), ucOC/tOC and cOC/tOC ratios were calculated. Ageing was associated with a “U” shaped pattern for tOC, cOC and ucOC levels. The ucOC/tOC ratio was higher, while cOC/tOC ratio was lower, in men of advanced age, demonstrating that OC ratios may be better measures than the absolute values to identify age-related changes in OC. Study 2: to test the hypothesis that the serum ucOC absolute value and ucOC/tOC ratio are associated with muscle function and long-term risk for falls-related hospitalisations using a large longitudinal dataset (15 years) in older women (n=1261, mean age 75.2±2.7 years). In older women, a higher ucOC/tOC ratio was related to poorer physical function, including the long-term decline in physical function and increased risk of falls-related hospitalisations. Early The identification of women at higher risk for functional decline using the ucOC/tOC ratio may enable prevention and intervention strategies to occur early, reducing future risk for injurious falls. Study 3: to perform a systematic review to examine the effects of acute exercise on BTMs in adults over the age of 50 years and identify whether BTM responses are determined by exercise mode, intensity, age and sex. Thirteen studies were included: eight in middle-aged adults (n= 275, 212 women/63 men, mean age= 57.9±1.5 years) and five in older adults (n= 93, 50 women/43 men, mean age= 68.2±2.2 years). Eleven studies included aerobic exercise (AE) (7 middle-aged/4 older adults) and two included resistance exercise (RE) (both in middle-aged adults). AE increased C-terminal telopeptide of type I collagen (CTX), alkaline phosphatase (ALP) and bone-ALP in middle-aged and older adults. AE also increased tOC in middle-aged men, and procollagen I carboxyterminal propeptide (PICP) and cross‐linked carboxyterminal telopeptide of type I collagen (ICTP) in older women. In middle-aged adults, RE combined with impact exercise (jumping) had no effect on tOC or BALP, but led to a decrease in CTX. Jumping alone increased P1NP and tOC in middle-aged women. Acute exercise is an effective tool to modify BTMs, but the response appears to be specific to exercise modality, intensity, age and sex. Study 4: to test the hypotheses that a) at baseline, serum ucOC and other BTMs are associated with muscle function, b) acute exercise can alter ucOC and BTMs and c) muscle function at baseline is related to the acute exercise responses of these biomarkers. A total of 35 older adults (25 females/10 males, 72±6 years) participated. The baseline assessments included: body composition, handgrip strength and a physical performance test (PPT) (gait speed, TUG, time to climb and descend 10 stairs). Leg muscle quality (LMQ) and stair climb power (SCP) were calculated. Participants performed in a randomised order a single session of 30 mins AE (cycling at 70% of peak heart rate) and RE (leg press at 70% of one repetition maximum and jumping regimen). At baseline, higher muscle strength was associated with higher P1NP and better physical performance (lower PPT score). Similarly, higher SCP was associated with higher P1NP and the betafragment of CTX (ß-CTX) (p<0.05). Exercise, regardless of mode, decreased ß-CTX and tOC (all p<0.05), while P1NP and ucOC were not altered. Post-exercise, lower ß-CTX was associated with higher baseline muscle strength and power. Poorer baseline mobility was associated with higher ß-CTX. Independent of exercise mode, acute exercise decreased ß-CTX and tOC. Our data suggests that in older adults the relationship between muscle quality and function and BTMs is not specific to ucOC, but to BTMs in general. Furthermore, increased BTM levels were linked to better muscle function. General conclusions: Overall, the data from this thesis strengthen the evidence for bone-muscle interaction, but mechanisms behind this crosstalk remain unclear. Larger randomised controlled trials, as well as longitudinal epidemiological studies, are required to elucidate the link between both ucOC and BTMs with muscle function, as well as with exercise-induced responses. Whether the assessment of ucOC or the ucOC/tOC ratio should be added to the standard screening in clinical care for the early identification of people who are at risk of falls and fractures needs to be evaluated further.

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