Muscle energy recovery may explain fatigue in cancer survivors

Even apparently healthy cancer survivors often complain of extreme fatigue. They have finished treatment, the scans are clear, but they feel hollowed out, unable to walk to the mailbox or stay awake through dinner. 

The languor can linger for years, making it a major, unexplained symptom that clinicians have only been able to measure with subjective, imprecise surveys. 

But a pilot study published in Biomedicines may help clinicians obtain a better measurement tool that could eventually lead to better treatments.

Researchers at Rutgers University, Johns Hopkins University and the National Institute on Aging used a specialized MRI to peer directly into the skeletal muscle cells of 11 cancer survivors, measuring how quickly their mitochondria – the organelles that generate cellular fuel – rebuilt energy reserves after exertion.

No one before this had looked deeply into single-cell-specific biology that can drive cancer patient experiences. There is some previous work on blood mitochondrial levels, but blood composition shifts constantly. Every time you sneeze, your blood cells differ."

Leorey Saligan, study's senior author, professor and the vice dean of research, Rutgers School of Nursing

Saligan is also a member of the Cancer Prevention and Control Program at Rutgers Cancer Institute, the state's only NCI-designated Comprehensive Cancer Center, together with RWJBarnabas Health.

The team used a National Institutes of Health-validated MRI test for mitochondrial measurement called phosphorus-31 magnetic resonance spectroscopy (31P-MRS). Participants lay inside a scanner with a coil over their left thighs. After a brief, vigorous knee extension exercise to deplete energy stores, the scanner tracked recovery. A longer recovery time signals weaker mitochondrial function.

The 11 participants, whose ages ranged from 34 to 70, had undergone treatment for various cancers with surgery, chemotherapy, radiation, immunotherapy, hormone therapy or some combination.

Participants 65 and older exhibited about 10% slower muscle energy recovery than younger patients, along with weaker grip strength, higher self-reported fatigue and fewer daily steps. Treatment type also predicted muscle recovery to some extent, though treatment categories overlapped, and most participants had received more than one therapy. Participants who had received immunotherapy reported more fatigue, had slower muscle recovery, weaker grip strength and fewer daily steps than those who hadn't.

The most provocative finding was a counterintuitive one. Among younger participants, those with worse mitochondrial recovery reported less fatigue, not more. At the same time, worse mitochondrial recovery in that group correlated with higher resilience and coping self-efficacy. The researchers cautioned that this could reflect statistical instability in such a small sample. Still, it also raises the possibility that subjective fatigue and cellular energy capacity operate through partially distinct pathways.

"It just shows that the subjective experience of fatigue is very multidimensional," Saligan said. "It's not only the physical aspect that's dictating that symptom experience."

The study has significant limitations, including the small sample size and the mix of cancer types and treatments.

The value of the study, the researchers said, lies in demonstrating the feasibility of this approach. If 31P-MRS can provide a stable, noninvasive measure of mitochondrial function in cancer survivors, it could eventually serve as a biomarker linking the biology of post-treatment fatigue to the subjective experience cancer patients describe.

Saligan said the next step is to replicate the work with larger cohorts. A further goal would be to measure energy recovery in the brain and skeletal muscle simultaneously.

"It is really important to see how soon exercise can really accelerate recovery of the muscles, but also utilization of the energy in the muscles," Saligan said. "I think that is really critical for exercise dosing, but also timing exercise programs, for survivors."