Muscular aging and its relation to physical activity and function : longitudinal and cross-sectional analyses

With age, muscle mass decreases and muscle function and strength decline, which is associated with loss of independence, hospitalization, morbidity and mortality. The aim of this thesis was to investigate the mechanisms involved in the age-related loss of muscle mass, physical function and strength by 1) studying gene expression and muscle morphology in muscle biopsies of vastus lateralis longitudinally (Study I) and muscle morphology cross-sectionally (Study II) in a cohort of older men, i.e. the Uppsala Longitudinal Study of Adult Men (ULSAM, Study I and II), and in men with a lifelong history of endurance training (Study II), 2) evaluation of a semi-automated and manual method to analyze the cross-sectional area and radiological attenuation (RA) of eight lower extremity muscle groups in mobility-limited individuals aged over 70 years (Study III), 3) evaluation of the effect of a 6-month physical activity intervention on muscle size and density of the same locomotor muscles, with or without an oral nutritional supplement containing protein and vitamin D (study IV). In study I, muscle morphology including fiber types, fiber area, and satellite cells (SC) and 14 genes involved in muscle remodeling were analyzed at ages 70 and 88-90 years. Study II examined muscle morphology in seven elite endurance athletes aged 82-92 and 19 ULSAM men aged 87-91 years, who were divided into high and low function groups based on tests for physical function and strength. In Study III and IV, measurements were done in a cohort of mobility limited individuals over 70 years (the Vitality, Independence, and Vigor in the Elderly 2 Study, VIVE2). Eight different locomotor muscles were measured using both the semi-automated and manual method and two independent observers performed the manual measurements (Study III) and manual measurement only (Study IV).

In Study I, type II fibers decreased with age, whereas fibers co-expressing myosin heavy chain type I+IIA increased. Expression of genes involved in muscle remodeling were higher at age 70 compared to healthy adult men. Some of these genes were also expressed at higher levels at age 70 than at age 88-90 and in those who survived beyond age 82 compared to those who died before that age. The higher expression of genes involved in remodeling at age 70 in survivors were considered beneficial since muscle mass was relatively stable between 82 and 88 years. Lifelong endurance training was associated with a better oxidative profile, with more type I fibers, more capillaries and fewer COX negative fibers even after 80 years of age (Study II). Manual and semi-automated measurements of area and RA correlated well between methods, especially in normal-density muscles, as shown in study III. A 6-month physical activity intervention increased area and RA in some but not all muscle groups and these changes were not related to the more pronounced changes observed in physical function (study IV). In conclusion, muscle plasticity decreases in very old men, as evidenced by altered gene expression profile. Morphological characteristics are to some extent unrelated to physical function, while lifelong endurance training is associated with some beneficial morphological features even at very advanced ages. There is also a reduced muscular adaptive response to physical activity in old men and women and these changes are at least partially unrelated to physical function.

List of scientific papers

I. Elisabeth Skoglund*, Max Grönholdt-Klein*, Eric Rullman*, Lars-Eric Thornell, Anna Strömberg, Anu Hedman, Tommy Cederholm, Brun Ulfhake and Thomas Gustafsson. Longitudinal Muscle and Myocellular Changes in Community-Dwelling Men Over Two Decades of Successful Aging—The ULSAM Cohort Revisited. J Gerontol A Biol Sci Med Sci. 2020, 75, 654-663. *Shared first authorship.
https://doi.org/10.1093/gerona/glz068

II. Elisabeth Skoglund, Per Stål, Tommy R Lundberg, Eric Rullman, Thomas Gustafsson, Per A Tesch, Lars-Eric Thornell. Skeletal muscle morphology, satellite cells and oxidative profile in relation to physical function and lifelong endurance training in very old men. [Manuscript]

III. Hans E Berg, Daniel Truong, Elisabeth Skoglund, Thomas Gustafsson, Tommy R Lundberg. Threshold‐automated CT measurements of muscle size and radiological attenuation in multiple lower‐extremity muscles of older individuals. Clin Physiol Funct Imaging. 2020, 40, 165-172.
https://doi.org/10.1111/cpf.12618

IV. Elisabeth Skoglund, Tommy R Lundberg, Eric Rullman, Roger A. Fielding, Dylan R Kirn, Davis A Englund, Åsa von Berens, Afsaneh Koochek, Tommy Cederholm, Hans E Berg, Thomas Gustafsson. Functional improvements to 6 months of physical activity are not related to changes in size or density of multiple lower-extremity muscles in mobility-limited older individuals. [Submitted]