The functional consequences of fat accumulation in muscle

Decellularized muscle was stained with BODIPY, imaged with confocal microscopy and digitally reconstructed to generate this 3-D map of intramuscular fat.

The accumulation of adipocytes within skeletal muscle is a nearly ubiquitous feature of muscle pathology – associated with conditions as diverse as aging, diabetes and tendon injury.  Though this fat accumulation is frequently associated with poor muscle strength in humans, a direct link has not been established due to systemic disease pressures that simultaneously affect muscle cells.  Recently, we have developed methodology for high-resolution mapping of intramuscular adipocytes in mouse muscle that we are using in conjunction with precision ex-vivo analysis of muscle contractile performance to define the direct effect of fat accumulation on muscle function.  Ongoing work in this area is investigating the effect of fat accumulation on hypertrophic signaling and the potential for dynamic forces (resistance exercise) to reverse this pathology.

The role of fat phenotype in fat-muscle cross-talk

A transplanted graft of brown fat next to the supraspinatus muscle of the rotator cuff stained for perilipin (green) and UCP1 (red).

The way we think about the function of fat in the body has changed dramatically over the past 10 years.  Fat is now recognized as one of the  most important endocrine regulators of body physiology – affecting a diversity of cells from neurons to osteoblasts.  However, despite the close proximity of muscle and fat (specifically inter-muscular adipose tissue – IMAT), we know very little about how these tissues might signal each other locally.  To explore this important question, we have developed an inter-muscular fat transplant model in the mouse where we can alter fat phenotype and genotype to study the factors that influence fat-muscle cross-talk.  Ongoing work on this project is exploring the role of brown and browned-beige fat signaling on muscle degeneration and regeneration in the rotator cuff.  It is our hope that defining these interactions will lead to fat-targeted therapies in rotator cuff tears where excessive accumulation of beige fat is impeding muscle functional recovery.

The cellular basis for poor muscle performance in diabetic peripheral neuropathy

Histological image of a biopsy from an individual with diabetic peripheral neuropathy demonstrating fat infiltration (white circles).

The accumulation of intramuscular fat is dramatic in diabetic peripheral neuropathy – replacing as much as 90% of the volume of muscles of the foot and calf.  To better understand the interaction between these intramuscular adipocytes and neighboring muscle fibers in humans, we are obtaining biopsies from participants undergoing amputation, separating the muscle and fat components and isolating progenitor cells.  Using these cells we can generate patient-specific co-culture models to study paracrine secreted factors from intramuscular fat and how those signals regulate myogenesis.

Guiding cell-based therapies to prevent fibrosis

An APC immunostained for actin (green) and YAP (red). Defined actin stress fibers and nuclear YAP localization are typical of APCs grown on stiff substrates. These cells secrete more connective tissue matrix and exhibit signs of switching to a pro-fibrotic myofibroblast phenotype.

Fibrosis is a prevalent and debilitating feature of soft tissue injury. Current treatment strategies are unable to fully prevent tissue fibrosis and frequently individuals are left with decreased range of motion and functional deficits. Currently, we are working on a contracture prevention strategy that inhibits the fibrotic response of the anterior capsule in a rat model of elbow contracture by injecting mechanically primed adipose progenitor cells (APCs). Specifically, we culture APCs for 2 weeks on a soft substrate, mimicking a non-fibrotic environment, to induce a “mechanical memory” which they retain for 1 week when transferred to a stiff environment. In this approach, we hope to pre-program cells to remodel an injury environment away from a fibrotic state – a departure from injecting naive cells which can contribute to pathology through aberrant differentiation.