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Basic and clinical muscle biology - About our research

For more than four decades, my research group has studied the effects of aging on skeletal muscle function and size (sarcopenia) in humans and in experimental models.

Sarcopenia

For more than four decades, my research group has studied the effects of aging on skeletal muscle function and size (sarcopenia) in humans and in experimental models.

Specific interest has been focused on regulation of contraction at the muscle, motor unit, muscle fiber and motor protein levels and how muscle function is influenced by contractile protein isoform expression and post-translational modifications.

In order to achieve these goal, we have modified or developed research methods to study skeletal muscle from both humans and rodents, such as:

  1. Improving the glycogen-depletion technique to visualize and identify motor unit fibers, their spatial organization and myofibrillar protein isoform expression.
  2. Introducing the skinned fiber preparation for the study of regulation of human muscle fibers in relation to myofibrillar protein isoform expression and the development of a cryo-protection procedure allowing long-term storage of membrane permeabilized muscle fiber bundles without affecting regulation of muscle contraction (longest observation period to date exceeds 10 years of storage at -160 0C)
  3. Development of a single muscle fiber in vitro motility assay where myosin is extracted from a 1 mm long muscle fiber segment allowing detailed studies of the function of specific myosin isoforms (catalytic properties or motility speed as well as force generation capacity) without interference from structural or regulatory proteins.
  4. A method to determine the 3D organization of individual myonuclei along the length of individual muscle fibers and calculating the cytoplasmic volume supported by each myonucleus by using confocal imaging, 3D reconstructions and a novel algorithm.

Publications

CIM

After diagnosing the first intensive care unit (ICU) patient in Scandinavia with critical illness myopathy (CIM) while being on call Christmas 1995, the research focusing on improving our understanding of basic underlying mechanisms, improving diagnosis and monitoring, implementing and evaluating intervention strategies of CIM in experimental models, and translating promising interventions to the clinic has become the dominating research in my group.

This work has involved the modification of a very powerful and unique rat experimental model, originally developed by Dr. B. Dworkin at Rockefeller, to make it minimally invasive and suitable for the study of skeletal muscle.

This model is not limited by early mortality and I have collaborated with Dr. Dworkin using this model for two decades, originally at the Pennsylvania State University, later at Uppsala University and currently at Karolinska Institutet. After his retirement from Penn State, Dr. Dworkin joined my research group in Sweden and we now have the only two models of this experimental set-up available worldwide allowing us to conduct two long-term studies in parallel.

The hallmark of CIM is the preferential loss of the motor protein myosin, but we have also shown that the ICU condition induces significant post-translational modifications of myosin with a strong negative impact on myosin function.

The current collaboration with Professor J.L. Kirkland since more than two years has been supported by a seed grant from the Mayo-Karolinska Foundation.

The focus of this collaboration has been on the two factors which most strongly predict mortality and morbidity in ICU patients, i.e., old age and muscle wasting, with the aim of introducing novel pharmacological interventions targeting these two triggering factors.

Publications

Adaptability

The effects of chronic overuse, unloading and thyroid hormone exposure on regulation of muscle contraction and myofibrillar protein isoform expression have been investigated at the muscle cell and motor protein levels.

Our understanding of regulation of muscle contraction is based on observations in amphibians and small mammals, but there are significant species-differences related to body size. The applicant has therefore investigated the impact of body size on regulation of muscle contraction at the cell and motor protein levels and myonuclear organization in mammalian species with a 100,000-fold range in body mass (ranging from the mouse to the rhinoceros and including humans) with the aim of improving our understanding of human muscle function.

Publications

Methods

In order to understand the mechanisms underlying the impaired function in patients with different underlying conditions affecting muscle functions, such as myosinopathies, sarcopenia, critical illness myopathy, and neuropathies, different methods have been developed/modified to study regulation of muscle contraction in detailed under controlled conditions in the small muscle fiber segments obtained from percutaneous muscle biopsies in humans or from rodent muscles.

Publications

Experimental models

In order to unravel basic mechanisms underlying pathophysiological changes associated with aging, critical illness myopathy and hereditary myopathies affecting contractile proteins a significant effort has be devoted to the development/modification of different experimental models, such as:

  1. the glycogen depletion method where improvements have been made in the experimental set-up, the technique for enhancing glycogen depletion, quantitative methods for measuring enzyme activities in individual motor unit fibers, introduction of immunohistochemistry to identify myosin heavy chain isoforms and a computerized model to determine the spatial organization of motor unit fibers
  2. an experimental porcine ICU model where animals were exposed to different triggering factors for 5 days, and
  3. an experimental rat ICU model not limited by early mortality and the longest duration a rat has been monitored in this model to date is 96 days
  4. In time-resolved analyses, detailed analyses of gene/protein expression, protein modifications and regulation of muscle contraction have been investigated at durations varying from 6h to 14 days. Conventional rat ICU models cannot maintain life support for longer than a day or two adding a significant confounding factor, i.e. a deteriorating preparation.

Publications

Research support

  • Swedish Research Council (continuous 30 year funding)
  • Erling Persson Foundation
  • Alf
  • Karolinska Institutet

Contact

Professor/överläkare

Lars Larsson

Telefon: 08-524 872 95
Enhet: Larsson Lars grupp - Basal- och klinisk muskelbiologi
E-post: lars.larsson@ki.se