New Hospital Study Shows Gene Therapy Reverses Muscle Aging

Researchers show that targeting a growth factor gene in muscle preserves muscle integrity and physical fitness in mice with sarcopenia - the age-related loss of muscle mass and strength.

Key Points:

Genetically increasing the activity of neurotrophin 3 – a growth factor protein that facilitates neuron cell survival and differentiation – in the muscle of aged mice with sarcopenia boosts physical function.
NT-3 gene therapy preserves the integrity of muscle fibers, leading to increased size.

One of the most increasingly pervasive diseases that continues to cripple the elderly population is sarcopenia, a condition characterized by the gradual loss of muscle mass, strength, and function. Although the underlying mechanisms behind this debilitating age-related disease remain unclear, new research from Nationwide Children’s Hospital (NCH) in Ohio suggests that the growth factor protein neurotrophin 3 (NT-3) is a potential genetic target for preserving muscle integrity.

Ozes and colleagues from NCH report in the journal Aging-US that increasing NT-3 activity in the muscle of mice with sarcopenia through gene therapy leads to improved physical fitness, motor coordination, and muscle contraction. What’s more, NT-3 gene therapy increased the size of muscle fibers and attenuated the decline in type II muscle fibers, a common feature of sarcopenia.

NT-3 Gene Therapy Enhances Physical Function

Sarcopenia unavoidably exacerbates the dwindling of muscles, eventually leading to impaired physical ability and loss of independence. In efforts to thwart this degenerative disease, researchers have focused on interventions known to stimulate muscle growth and repair, namely strength training and healthy diets. Now, Ozes and colleagues explored whether gene therapy can ameliorate features of sarcopenia.

In the present study, the NCH researchers utilized muscle-targeted gene therapy to increase the activity of NT-3, which has been shown to hold anti-inflammatory and mitochondrial-boosting properties vital to muscle health and maintenance. To evaluate the effects of NT-3 gene therapy on physical function, the investigators employed the exhaustion treadmill test and the rotor rod test.

Compared to untreated aged sarcopenic mice, those that received NT-3 gene therapy exhibited superior endurance, running longer distances with less exhaustion. Furthermore, treated mice spent significantly more time on the rotating rod than untreated aged sarcopenic mice, highlighting enhanced motor coordination. Notably, NT-3 gene therapy also improved muscle contractions, which are essential for maintaining movement and posture as we age. These initial findings suggest that increasing NT-3 activity in muscles protects against sarcopenia-induced muscle dysfunction.

(Ozes et al., 2023 | *Aging-US*) **NT-3 therapy improves endurance and motor coordination.** Left: Treated mice (NT-3) performed a treadmill test two months (2m), four months (4m), and six months (6m) post-NT-3 injection (PI) and ran longer distances than untreated mice (UT). Right: NT-3 mice spent more time on the rotating rod than UT.

NT-3 Gene Therapy Restores Muscle Fibers

Muscle fibers (the muscle cells that compose our muscles) support vital functions like movement, circulation, and joint stability, and they are divided into three classes: slow oxidative (SO), fast oxidative (FO), or fast glycolytic (FG). SO fibers are categorized as type 1 fibers, which are fatigue-resistant and suitable for endurance exercises. Conversely, FO and FG fibers are categorized as type 2 fibers, which are less fatigue-resistant but more fitted for strength exercises that require quick, high bursts of energy. These fibers inevitably crumble with age, and studies show that individuals with sarcopenia exhibit significant decreases in type 2 muscle fibers.

With this in mind, Ozes and colleagues examined whether NT-3 gene therapy could ameliorate muscle fiber degradation in aged sarcopenic mice. The investigators found that NT-3-treated mice displayed significantly more type 2 muscle fibers than untreated mice. Additionally, both type 1 and 2 muscle fibers were larger in mice receiving NT-3 gene therapy. Overall, the findings demonstrate that targeting NT-3 in muscles is sufficient to restore muscle fiber health.

(Ozes et al., 2023 | *Aging-US*) **NT-3 gene therapy increases muscle fiber size.** Mice that received NT-3 gene therapy (NT-3) had larger slow oxidative (STO), fast oxidative (FTO), and fast glycolytic (FTG) fibers than untreated mice (UT). NT-3 mice had similar muscle fibers to young 10-month-old wild-type mice.

Is Gene Therapy the Key to Longevity?

Gene therapy is quite unique, as it has the potential to prolong longevity and address a wide range of age-related conditions stemming from genetic alterations or defects. Animal studies have already shown that age-related conditions like eye degeneration, cancer, and now sarcopenia can be targeted via gene therapy. Moreover, many preclinical studies have shown that increasing the activity of specific genes (VEGF, TERT, SIRT6, FST) effectively prolongs lifespan. Although the available research has sparked excitement in the aging field, gene therapy has a few more hurdles to clear before becoming a widespread longevity intervention. That being said, it appears that gene therapy has potent effects on health.